Administration of benzodiazepine compositions

ABSTRACT

The invention relates to pharmaceutical compositions comprising one or more benzodiazepine drugs for nasal administration, methods for producing and for using such compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.13/495,942, filed Jun. 13, 2012, which is a Continuation-in-Part of U.S.patent application Ser. No. 12/413,439, filed Mar. 27, 2009, publishedas US 2009/0258865 on Oct. 15, 2009, which is incorporated herein byreference in its entirety, and which claims priority to U.S. provisionalapplication 61/040,558, filed Mar. 28, 2008, which is incorporatedherein by reference; U.S. patent application Ser. No. 13/495,942, filedJun. 13, 2012, also claims priority to U.S. provisional application61/497,017, filed Jun. 14, 2011 and U.S. provisional application61/570,110, filed Dec. 13, 2011, each of which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

This application relates to the nasal administration of benzodiazepinedrugs and combinations thereof.

BACKGROUND OF THE INVENTION

By way of non-limiting example, the benzodiazepine family consists ofdrugs such as diazepam, lorazepam, and midazolam. The drugs in thisfamily have been observed as possessing sedative, tranquilizing andmuscle relaxing properties. They are frequently classified as anxiolyticand skeletal muscle relaxants. They are thought to be useful inpreventing, treating, or ameliorating the symptoms of anxiety, insomnia,agitation, seizures (such as those caused by epilepsy), muscle spasmsand rigidity, the symptoms of drug withdrawal associated with thecontinuous abuse of central nervous system depressants, and exposure tonerve agents.

Benzodiazepines are thought to act by binding to the GABA_(A) receptorof a neuron, possibly causing the receptor to change shape and making itmore accessible to gamma-aminobutyric acid (GABA).

GABA is an inhibitory neurotransmitter that, when bound to the GABA_(A)receptor, facilitates Cl⁻ ions flooding into the neuron to which thereceptor is bound. The increase in Cl⁻ ions hyperpolarizes the membraneof the neuron. This completely or substantially reduces the ability ofthe neuron to carry an action potential. Targeting this receptor isparticularly useful in treating many disorders, such as tetanus andepilepsy, which may result from too many action potentials proceedingthrough the nervous system.

Current formulations of benzodiazepine drugs can be administered orally,rectally, or parenterally. The ability to utilize these and other typesof formulations has been significantly limited due, in many cases, tosolubility challenges.

The oral route of administration may be considered sub-optimal due toseveral disadvantages. For example, the amount of time required for anorally administered benzodiazepine drug to reach therapeuticallyrelevant concentrations in blood plasma may be rather long, such as anhour or more. Moreover, as benzodiazepine drugs pass through the liver asignificant amount of the drug may be metabolized. Thus, large doses maybe required to achieve therapeutic plasma levels. Furthermore, due tothe nature of seizures and muscle spasms, it can be extremely difficultfor either a patient or a care-giver to administer the benzodiazepinedrug orally and care-givers may be reluctant to place their hands inpatients' mouths.

Intravenous administration perhaps provides a faster route ofadministration. However intravenous administration is generally limitedto trained health care professionals in tightly controlled clinicalsettings. Additionally, sterility must be maintained. Furthermore,administering any drug intravenously can be painful and is likelyimpractical for patients suffering from a phobia of needles. Inaddition, intravenous administration of benzodiazepines is associatedwith respiratory depression. Thus, use of intravenous benzodiazepines islimited to professional health care environments.

Rectal suppository compositions of benzodiazepine drugs can have a rapidonset of action. However, the inconvenience of rectally administereddrug is an obvious impediment to their being administered by anyoneoutside a very small group of the patient's intimate acquaintances andthe patient's professional medical care-givers.

SUMMARY OF THE INVENTION

In some embodiments, there are provided (non-aqueous) pharmaceuticalsolutions for nasal administration consisting of: (a) a benzodiazepinedrug; (b) one or more natural or synthetic tocopherols or tocotrienols,or any combinations thereof, in an amount from about 30% to about 95%(w/w); (c) one or more alcohols or glycols, or any combinations thereof,in an amount from about 10% to about 70% (w/w); and (d) an alkylglycoside, in a pharmaceutically-acceptable solution for administrationto one or more nasal mucosal membranes of a patient. In someembodiments, the benzodiazepine drug is dissolved in the one or morenatural or synthetic tocopherols or tocotrienols, or any combinationsthereof, in an amount from about 30% to about 95% (w/w); and the one ormore alcohols or glycols, or any combinations thereof, in an amount fromabout 10% to about 70% (w/w). In some embodiments, the benzodiazepinedrug is selected from the group consisting of: alprazolam, brotizolam,chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam,diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam,medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam,triazolam, temazepam, loprazolam, any pharmaceutically-acceptable saltsthereof, and any combinations thereof. In some embodiments, thebenzodiazepine drug is diazepam, or a pharmaceutically-acceptable saltthereof. In some embodiments, the solution contains about 1 to about 20%(w/v) of benzodiazepine, e.g. about 1 to about 20% (w/v) of diazepam. Insome embodiments, the one or more natural or synthetic tocopherols ortocotrienols are selected from the group consisting of: α-tocopherol,β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol,γ-tocotrienol, δ-tocotrienol, tocophersolan, any isomers thereof, anyesters thereof, any analogs or derivatives thereof, and any combinationsthereof. In some embodiments, the one or more alcohols are selected fromthe group consisting of: ethanol, propyl alcohol, butyl alcohol,pentanol, benzyl alcohol, any isomers thereof, or any combinationsthereof. In some embodiments, the solution contains two or morealcohols, such as ethanol (1-25% (w/v)) and benzyl alcohol (1-25%(w/v)), or ethanol (10-22.5% (w/v)) and benzyl alcohol (7.5-12.5%(w/v)). In some embodiments, the benzodiazepine is present in thepharmaceutical composition in a concentration from about 20 mg/mL toabout 200 mg/mL. In some embodiments, the one or more natural orsynthetic tocopherols or tocotrienols, or any combinations thereof, isin an amount from about 45% to about 85% (w/w). In some embodiments, theone or more natural or synthetic tocopherols or tocotrienols, or anycombinations thereof, is in an amount from about 50% to about 75% (w/w).In some embodiments, the one or more alcohols or glycols, or anycombinations thereof, is in an amount from about 15% to about 55% (w/w),e.g. about 25% to about 40% (w/w). In some embodiments, the solutionconsists of diazepam (5-15% (w/v)), alkyl glycoside (0.01-1% (w/v)),vitamin E (45-65% (w/v)), ethanol (10-25% (w/v)) and benzyl alcohol(5-15% (w/v)). In some embodiments, the solution comprises at leastabout 0.01% (w/w) of an alkyl glycoside, e.g. about 0.01% to 1% (w/w) ofan alkyl glycoside, such as dodecyl maltoside. In some embodiments, thesolution consists of diazepam (5-15% (w/v)), dodecyl maltoside (0.01-1%(w/v)), vitamin E (45-65% (w/v)), ethanol (10-25% (w/v)) and benzylalcohol (5-15% (w/v)); more particularly the solution may consist ofdiazepam (9-11% (w/v)), dodecyl maltoside (0.1-0.5% (w/v)), vitamin E(50-60% (w/v)), ethanol (15-22.5% (w/v)) and benzyl alcohol (7.5-12.5%(w/v)); and even more particularly, the solution may consist of diazepam(10% (w/v)), dodecyl maltoside (0.15-0.3% (w/v)), vitamin E (50-60%(w/v)), ethanol (17-20% (w/v)) and benzyl alcohol (10-12% (w/v)).

Some embodiments described herein provide a method of treating a patientwith a disorder which may be treatable with a benzodiazepine drug,comprising: administering to one or more nasal mucosal membranes of apatient a pharmaceutical solution for nasal administration consisting ofa benzodiazepine drug, one or more natural or synthetic tocopherols ortocotrienols, or any combinations thereof, in an amount from about 30%to about 95% (w/w); one or more alcohols or glycols, or any combinationsthereof, in an amount from about 10% to about 70% (w/w); and an alkylglycoside. In some embodiments, the benzodiazepine drug is dissolved inthe one or more natural or synthetic tocopherols or tocotrienols, or anycombinations thereof, in an amount from about 30% to about 95% (w/w);and the one or more alcohols or glycols, or any combinations thereof, inan amount from about 10% to about 70% (w/w). In some embodiments, thebenzodiazepine drug is selected from the group consisting of:alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam,clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam,midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam,prazepam, quazepam, triazolam, temazepam, loprazolam, anypharmaceutically-acceptable salts thereof, and any combinations thereof.In some embodiments, the benzodiazepine drug is diazepam, or apharmaceutically-acceptable salt thereof. In some embodiments, thesolution contains about 1 to about 20% (w/v) of benzodiazepine, e.g.about 1 to about 20% (w/v) of diazepam. In some embodiments, the one ormore natural or synthetic tocopherols or tocotrienols are selected fromthe group consisting of: α-tocopherol, β-tocopherol, γ-tocopherol,δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol,δ-tocotrienol, tocophersolan, any isomers thereof, any esters thereof,any analogs or derivatives thereof, and any combinations thereof. Insome embodiments, the one or more alcohols are selected from the groupconsisting of: ethanol, propyl alcohol, butyl alcohol, pentanol, benzylalcohol, any isomers thereof, or any combinations thereof. In someembodiments, the solution contains two or more alcohols, such as ethanol(1-25% (w/v)) and benzyl alcohol (1-25% (w/v)), or ethanol (10-22.5%(w/v)) and benzyl alcohol (7.5-12.5% (w/v)). In some embodiments, thebenzodiazepine is present in the pharmaceutical composition in aconcentration from about 20 mg/mL to about 200 mg/mL. In someembodiments, the one or more natural or synthetic tocopherols ortocotrienols, or any combinations thereof, is in an amount from about45% to about 85% (w/w). In some embodiments, the one or more natural orsynthetic tocopherols or tocotrienols, or any combinations thereof, isin an amount from about 50% to about 75% (w/w). In some embodiments, theone or more alcohols or glycols, or any combinations thereof, is in anamount from about 15% to about 55% (w/w), e.g. about 25% to about 40%(w/w). In some embodiments, the solution consists of diazepam (5-15%(w/v)), alkyl glycoside (0.01-1% (w/v)), vitamin E (45-65% (w/v)),ethanol (10-25% (w/v)) and benzyl alcohol (5-15% (w/v)). In someembodiments, the solution comprises at least about 0.01% (w/w) of analkyl glycoside, e.g. about 0.01% to 1% (w/w) of an alkyl glycoside,such as dodecyl maltoside. In some embodiments, the solution consists ofdiazepam (5-15% (w/v)), dodecyl maltoside (0.01-1% (w/v)), vitamin E(45-65% (w/v)), ethanol (10-25% (w/v)) and benzyl alcohol (5-15% (w/v));more particularly the solution may consist of diazepam (9-11% (w/v)),dodecyl maltoside (0.1-0.5% (w/v)), vitamin E (50-60% (w/v)), ethanol(15-22.5% (w/v)) and benzyl alcohol (7.5-12.5% (w/v)); and even moreparticularly, the solution may consist of diazepam (10% (w/v)), dodecylmaltoside (0.15-0.3% (w/v)), vitamin E (50-60% (w/v)), ethanol (17-20%(w/v)) and benzyl alcohol (10-12% (w/v)). In some embodiments, thepatient is human. In some embodiments, the benzodiazepine isadministered in a therapeutically effective amount from about 1 mg toabout 20 mg. In some embodiments, the benzodiazepine is administered asin a dosage volume from about 10 μL to about 200 μL. In someembodiments, the administration of the pharmaceutical compositioncomprises spraying at least a portion of the therapeutically effectiveamount of the benzodiazepine into at least one nostril. In someembodiments, the administration of the pharmaceutical compositioncomprises spraying at least a portion of the therapeutically effectiveamount of the benzodiazepine into each nostril. In some embodiments,administration of the pharmaceutical composition comprises spraying afirst quantity of the pharmaceutical composition into the first nostril,spraying a second quantity of the pharmaceutical composition into asecond nostril, and optionally after a pre-selected time delay, sprayinga third quantity of the pharmaceutical composition into the firstnostril. In some embodiments, the method further comprises, optionallyafter a pre-selected time delay, administering at least a fourthquantity of the pharmaceutical composition to the second nostril. Insome embodiments, nasal administration of the pharmaceutical compositionbegins at any time before or after onset of symptoms of a disorder whichmay be treatable with the pharmaceutical composition. In someembodiments, the treatment achieves bioavailability that is from about80-125% (e.g. about 90-110%, or more particularly about 92.5-107.5%) ofthat achieved with the same benzodiazepine administered intravenously,e.g. In this context, it is intended that bioavailability be determinedby a suitable pharmacodynamic method, such as comparison of area underthe blood plasma concentration curve (AUC) for the nasally andintravenously administered drug. It is further understood that thepercent bioavailability of the nasally administered benzodiazepine maybe determined by comparing the area under the blood plasma concentrationcurve obtained with one dose of the benzodiazepine (e.g. 10 mg of nasaldiazepam) with another dose of the same benzodiazepine administeredintravenously (e.g. 5 mg of i.v. diazepam), taking into considerationthe difference in dose. Thus, for the sake of illustration, a 10 mgnasal diazepam dose that achieves an AUC that is precisely half of theAUC obtained with 5 mg of i.v. diazepam would have a bioavailability of100%. In some embodiments, the disorder to be treated is a seizure, suchas an epileptic seizure, a breakthrough seizure, or other seizure. Insome embodiments, the solution and treatment with the solution aresubstantially non-irritating and well-tolerated.

In some embodiments, the pharmaceutical composition for nasaladministration comprises: a benzodiazepine drug; one or more natural orsynthetic tocopherols or tocotrienols, or any combinations thereof, inan amount from about 30% to about 95% (w/w); and one or more alcohols orglycols, or any combinations thereof, in an amount from about 5% toabout 70% (w/w), preferably about 10% to about 70% (w/w) in apharmaceutically-acceptable formulation for administration to one ormore nasal mucosal membranes of the patient. In some embodiments thebenzodiazepine drug is dissolved in the one or more natural or synthetictocopherols or tocotrienols, or any combinations thereof, in an amountfrom about 30% to about 95% (w/w); and the one or more alcohols orglycols, or any combinations thereof, in an amount from about 5% toabout 70% (w/w), preferably about 10% to about 70% (w/w). In someembodiments, the benzodiazepine drug is dissolved in a carrier system.In some embodiments, at least part of the benzodiazepine drug is in aform comprising benzodiazepine microparticles, nanoparticles orcombinations thereof. In some embodiments, the composition issubstantially free of benzodiazepine microparticles, nanoparticles orcombinations thereof.

In some embodiments, the benzodiazepine drug is selected from the groupconsisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam,clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam,halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam,lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, anypharmaceutically-acceptable salts thereof, and any combinations thereof.In some embodiments, the benzodiazepine drug is diazepam, or apharmaceutically-acceptable salt thereof. In some embodiments, thebenzodiazepine drug comprises benzodiazepine microparticles,nanoparticles, or combinations thereof. In some embodiments, thebenzodiazepine nanoparticles have an effective average particle size ofless than about 5000 nm. In some embodiments, the benzodiazepine drug issubstantially free of benzodiazepine microparticles, nanoparticles orcombinations thereof.

In some embodiments, the one or more natural or synthetic tocopherols ortocotrienols are selected from the group consisting of: α-tocopherol,β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol,γ-tocotrienol, δ-tocotrienol, tocophersolan, any isomers thereof, anyesters thereof, any analogs or derivatives thereof, and any combinationsthereof. In some embodiments, a synthetic tocopherol can include VitaminE TPGS (Vitamin E polyethylene glycol succinate). In some embodiments,on the other hand, synthetic tocopherols exclude tocopherols covalentlybonded or linked (e.g. through a diacid linking group) to a glycolpolymer, such as polyethylene glycol). Thus, in some embodiments, thecompositions described herein exclude Vitamin E TPGS.

In some embodiments, one or more alcohols are selected from the groupconsisting of: ethanol, propyl alcohol, butyl alcohol, pentanol, benzylalcohol, any isomers thereof, or any combinations thereof. In someembodiments, the one or more glycols are selected from the groupconsisting of: ethylene glycol, propylene glycol, butylene glycol,pentylene glycol, any isomers thereof, and any combinations thereof. Insome preferred embodiments, the glycols exclude glycol polymers. In somepreferred embodiments, the glycols exclude glycol polymers having anaverage molecular weight of greater than 200. In some embodiments, theglycols exclude polyethylene glycol having an average molecular weightof greater than about 200.

In some embodiments, the benzodiazepine drug is present in the carriersystem in a concentration from about 1 mg/mL to about 600 mg/mL. In someembodiments, the benzodiazepine drug is present in a carrier system in aconcentration from about 10 mg/mL to about 250 mg/mL. In someembodiments, the benzodiazepine is present in a carrier system in aconcentration from about 20 mg/mL to about 50 mg/mL.

In some embodiments, the carrier system comprises one or more natural orsynthetic tocopherols or tocotrienols, or any combinations thereof, inan amount from about 45% to about 85% (w/w). In some embodiments, thecarrier system comprises one or more natural or synthetic tocopherols ortocotrienols, or any combinations thereof, in an amount from about 60%to about 75% (w/w). In some embodiments, the carrier system comprisesone or more natural or synthetic tocopherols or tocotrienols, or anycombinations thereof, in an amount of about 70% (w/w).

In some embodiments, the carrier system comprises one or more alcoholsor glycols, or any combinations thereof, in an amount from about 10% toabout 70% (w/w). In some embodiments, the carrier system comprises oneor more alcohols or glycols, or any combinations thereof, in an amountfrom about 15% to about 55% (w/w). In some embodiments, the carriersystem comprises one or more alcohols or glycols, or any combinationsthereof, in an amount from about 25% to about 40% (w/w). In someembodiments, the carrier system comprises one or more alcohols orglycols, or any combinations thereof, in an amount of about 30% (w/w).

In some embodiments, the composition comprises at least one additionalingredient selected from the group consisting of: active pharmaceuticalingredients; enhancers; excipients; and agents used to adjust the pH,buffer the composition, prevent degradation, and improve appearance,odor, or taste.

In some embodiments, the composition comprises one or more additionalexcipients, such as one or more parabens, one or more povidones, and/orone or more alkyl glycosides.

The invention also discloses a method of treating a patient with adisorder that may be treatable with a benzodiazepine drug. In someembodiments, the patient is a human. In some embodiments, the methodcomprises: administering to one or more nasal mucosal membranes of apatient a pharmaceutical composition for nasal administration comprisinga benzodiazepine drug; one or more natural or synthetic tocopherols ortocotrienols, or any combinations thereof, in an amount from about 30%to about 95% (w/w); and one or more alcohols or glycols, or anycombinations thereof, in an amount from about 5% to about 70%,preferably about 10% to about 70% (w/w). In some embodiments, thebenzodiazepine is dissolved in the one or more natural or synthetictocopherols or tocotrienols, or any combinations thereof, in an amountfrom about 30% to about 95% (w/w); and the one or more alcohols orglycols, or any combinations thereof, in an amount from about 5% toabout 70%, preferably about 10% to about 70% (w/w). In some embodiments,the benzodiazepine drug is dissolved in a carrier system. In someembodiments, the benzodiazepine drug includes benzodiazepinemicroparticles, nanoparticles, or combinations thereof. In someembodiments, the composition is substantially free of benzodiazepinemicroparticles, nanoparticles or combinations thereof.

In some embodiments, the benzodiazepine drug is selected from the groupconsisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam,clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam,halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam,lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, or anypharmaceutically-acceptable salts thereof, and any combinations thereof.In some embodiments, the benzodiazepine drug is diazepam, or apharmaceutically-acceptable salt thereof. In some embodiments, thebenzodiazepine drug is fully dissolved in a single phase comprising oneor more one or more natural or synthetic tocopherols or tocotrienols andone or more alcohols or glycols. In some embodiments, the benzodiazepinedrug comprises benzodiazepine microparticles, nanoparticles, orcombinations thereof. In some such embodiments, the composition furthercomprises water. In some embodiments, the benzodiazepine nanoparticleshave an effective average particle size of less than about 5000 nm. Insome embodiments, the composition is substantially free ofbenzodiazepine microparticles, nanoparticles or combinations thereof.

In some embodiments, the one or more natural or synthetic tocopherols ortocotrienols are selected from the group consisting of: α-tocopherol,β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol,γ-tocotrienol, δ-tocotrienol, tocophersolan, any isomers thereof, anyesters thereof, any analogs or derivatives thereof, and any combinationsthereof.

In some embodiments, the one or more alcohols are selected from thegroup consisting of: ethanol, propyl alcohol, butyl alcohol, pentanol,benzyl alcohol, any isomers thereof, and any combinations thereof. Insome embodiments, the one or more glycols are selected from the groupconsisting of: ethylene glycol, propylene glycol, butylene glycol,pentylene glycol, any isomers thereof, and any combinations thereof. Insome embodiments, the alcohol or glycol is free of water (dehydrated,USP). In some embodiments, the alcohol is ethanol (dehydrated, USP).

In some embodiments, the benzodiazepine drug is present in the carriersystem in a concentration from about 1 mg/mL to about 600 mg/mL. In someembodiments, the benzodiazepine drug is present in the carrier system ina concentration of from about 10 mg/mL to about 250 mg/mL. In someembodiments, the benzodiazepine drug is present in the carrier system ina concentration of from about 20 mg/mL to about 50 mg/mL.

In some embodiments, the carrier system comprises one or more natural orsynthetic tocopherols or tocotrienols, or any combinations thereof, inan amount from about 45% to about 85% (w/w). In some embodiments, thecarrier system comprises one or more natural or synthetic tocopherols ortocotrienols, or any combinations thereof, in an amount from about 60%to about 75% (w/w). In some embodiments, the carrier system comprisesone or more natural or synthetic tocopherols or tocotrienols, or anycombinations thereof, in an amount of about 70% (w/w).

In some embodiments, the carrier system comprises one or more alcoholsor glycols, or any combinations thereof, in an amount from about 15% toabout 55% (w/w). In some embodiments, the carrier system comprises oneor more alcohols or glycols, or any combinations thereof, in an amountfrom about 25% to about 40% (w/w). In some embodiments, the carriersystem comprises one or more alcohols or glycols, or any combinationsthereof, in an amount from about 30% (w/w).

In some embodiments, the composition comprises at least one additionalingredient selected from the group consisting of: active pharmaceuticalingredients; enhancers; excipients; and agents used to adjust the pH,buffer the composition, prevent degradation, and improve appearance,odor, or taste.

In some embodiments, the composition is in a pharmaceutically-acceptablespray formulation, and further comprising administering the compositionto one or more nasal mucosal membranes of the patient. In someembodiments, the therapeutically effective amount is from about 1 mg toabout 20 mg of the benzodiazepine. In some embodiments, thepharmaceutical composition is in a pharmaceutically-acceptable sprayformulation having volume from about 100 μL to 200 μL.

In some embodiments, the administration of the composition comprisesspraying at least a portion of the therapeutically effective amount ofthe composition into at least one nostril. In some embodiments, theadministration of the composition comprises spraying at least a portionof the therapeutically effective amount of the composition into eachnostril. In some embodiments, the administration of the compositioncomprises spraying a first quantity of the composition into the firstnostril, spraying a second quantity of the composition into a secondnostril, and optionally after a pre-selected time delay, spraying athird quantity of the composition into the first nostril. Someembodiments further comprise, optionally after a pre-selected timedelay, administering at least a fourth quantity of the composition tothe second nostril.

In some embodiments, the administration of the composition begins at anytime before or after onset of symptoms of a disorder which may betreatable with the composition.

Additional embodiments, uses, and advantages of the invention willbecome apparent to the person skilled in the art upon consideration ofthe disclosure set forth herein.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

Some embodiments of the invention may be further appreciated uponconsideration of the appended drawings, of which:

FIG. 1 depicts a 240 hour linear plot of the arithmetic mean plasmaconcentration of diazepam after intranasal administration of 10 mg ofdiazepam as a suspension of Table 11-2, intranasal administration 10 mgof diazepam as a solution of Table 11-1, and 5 mg of diazepam as anintravenous injection.

FIG. 2 depicts a 240 hour semi-logarithmic plot of the arithmetic meanplasma concentration of diazepam after intranasal administration of 10mg of diazepam as a suspension of Table 11-2, intranasal administration10 mg of diazepam as a solution of Table 11-1, and 5 mg of diazepam asan intravenous injection.

FIG. 3 depicts a 24 hour linear plot of the arithmetic mean plasmaconcentration of diazepam after intranasal administration of 10 mg ofdiazepam as a suspension of Table 11-2, intranasal administration 10 mgof diazepam as a solution of Table 11-1, and 5 mg of diazepam as anintravenous injection.

FIG. 4 is a Flow Diagram for one embodiment of a process for themanufacture of a diazepam solution according to the instant invention.

FIG. 5 is a Flow Diagram for one embodiment of a process for themanufacture of a diazepam suspension according to the instant invention.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are pharmaceutical compositions of one or morebenzodiazepine drugs and methods of using such pharmaceuticalcompositions. Such pharmaceutical compositions are administered nasally.

In some embodiments, the pharmaceutical composition for nasaladministration comprises: a benzodiazepine drug; one or more natural orsynthetic tocopherols or tocotrienols, or any combinations thereof, inan amount from about 30% to about 95% (w/w); and one or more alcohols orglycols, or any combinations thereof, in an amount from about 10% toabout 70% (w/w) in a pharmaceutically-acceptable formulation foradministration to one or more nasal mucosal membranes of the patient. Insome embodiments the benzodiazepine drug is dissolved in the one or morenatural or synthetic tocopherols or tocotrienols, or any combinationsthereof, in an amount from about 30% to about 95% (w/w); and the one ormore alcohols or glycols, or any combinations thereof, in an amount fromabout 10% to about 70% (w/w). In some embodiments, the benzodiazepinedrug is dissolved in a carrier system. In some embodiments, at leastpart of the benzodiazepine drug is in a form of microparticles,nanoparticles, or combinations thereof. In some embodiments, thecomposition is substantially free of benzodiazepine microparticles,nanoparticles or combinations thereof.

In some embodiments, the pharmaceutical composition for nasaladministration comprises: a benzodiazepine drug; one or more natural orsynthetic tocopherols or tocotrienols, or any combinations thereof, inan amount from about 30% to about 95% (w/w); and one or more alcohols orglycols, or any combinations thereof, in an amount from about 5% toabout 70% (w/w) in a pharmaceutically-acceptable formulation foradministration to one or more nasal mucosal membranes of the patient. Insome embodiments the benzodiazepine drug is dissolved in the one or morenatural or synthetic tocopherols or tocotrienols, or any combinationsthereof, in an amount from about 30% to about 95% (w/w); and the one ormore alcohols or glycols, or any combinations thereof, in an amount fromabout 5% to about 70% (w/w). In some embodiments, the benzodiazepinedrug is dissolved in a carrier system. In some embodiments, at leastpart of the benzodiazepine drug is in a form of microparticles,nanoparticles, or combinations thereof. In some embodiments, thecomposition is substantially free of benzodiazepine microparticles,nanoparticles or combinations thereof.

In some embodiments, the benzodiazepine drug is selected from the groupconsisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam,clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam,halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam,lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, anypharmaceutically-acceptable salts thereof, and any combinations thereof.In some embodiments, the benzodiazepine drug is diazepam, or apharmaceutically-acceptable salt thereof. In some embodiments, thebenzodiazepine drug comprises benzodiazepine microparticles,nanoparticles, or combinations thereof. In some embodiments, thebenzodiazepine nanoparticles have an effective average particle size ofless than about 5000 nm. In some embodiments, the composition issubstantially free of benzodiazepine microparticles, nanoparticles orcombinations thereof.

In some embodiments, the one or more natural or synthetic tocopherols ortocotrienols are selected from the group consisting of: α-tocopherol,β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol,γ-tocotrienol, δ-tocotrienol, tocophersolan, any isomers thereof, anyesters thereof, any analogs or derivatives thereof, and any combinationsthereof. In some embodiments, the carrier system includes one or moresynthetic tocopherols having a polymer glycol covalently bonded orlinked to a tocopherol core, such as Vitamin E TPGS, which is describedin U.S. Pat. No. 6,193,985, which is incorporated herein by reference inits entirety. In particular, it has been found that in some particulatesuspensions of benzodiazepines, wherein the benzodiazepine is notdissolved in a tocopherol phase, Vitamin E TPGS can be a desirableexcipient for stabilizing the particulate (microparticle, nanoparticleor combination) suspension. In some embodiments, on the other hand, thecarrier system specifically excludes synthetic tocopherols having apolymer glycol covalently bonded or linked to a tocopherol core, such asVitamin E TPGS, which is described in U.S. Pat. No. 6,193,985, which isincorporated herein by reference in its entirety.

In some embodiments, one or more alcohols are selected from the groupconsisting of: ethanol, propyl alcohol, butyl alcohol, pentanol, benzylalcohol, any isomers thereof, or any combinations thereof. In someembodiments, the alcohol is ethanol (dehydrated, USP). In someembodiments, the one or more glycols are selected from the groupconsisting of: ethylene glycol, propylene glycol, butylene glycol,pentylene glycol, any isomers thereof, and any combinations thereof. Insome embodiments, the glycol is propylene glycol USP. In someembodiments, a synthetic tocopherol can include Vitamin E TPGS (VitaminE polyethylene glycol succinate). In some embodiments, on the otherhand, synthetic tocopherols exclude tocopherols covalently bonded orlinked (e.g. through a diacid linking group) to a glycol polymer, suchas polyethylene glycol). Thus, in some embodiments, the compositionsdescribed herein exclude Vitamin E TPGS.

In some embodiments, the benzodiazepine drug is present in the carriersystem in a concentration from about 1 mg/mL to about 600 mg/mL. In someembodiments, the benzodiazepine drug is present in a carrier system in aconcentration from about 10 mg/mL to about 250 mg/mL. In someembodiments, the benzodiazepine is present in a carrier system in aconcentration from about 20 mg/mL to about 50 mg/mL.

In some embodiments, the carrier system comprises one or more natural orsynthetic tocopherols or tocotrienols, or any combinations thereof, inan amount from about 45% to about 85% (w/w). In some embodiments, thecarrier system comprises one or more natural or synthetic tocopherols ortocotrienols, or any combinations thereof, in an amount from about 60%to about 75% (w/w). In some embodiments, the carrier system comprisesone or more natural or synthetic tocopherols or tocotrienols, or anycombinations thereof, in an amount of about 70% (w/w). In someembodiments, a synthetic tocopherol can include Vitamin E TPGS (VitaminE polyethylene glycol succinate). In some embodiments, on the otherhand, synthetic tocopherols exclude tocopherols covalently bonded orlinked (e.g. through a diacid linking group) to a glycol polymer, suchas polyethylene glycol). Thus, in some embodiments, the compositionsdescribed herein exclude Vitamin E TPGS.

In some embodiments, the carrier system comprises one or more alcoholsor glycols, or any combinations thereof, in an amount from about 10% toabout 55%, about 10% to about 40%, about 10% to about 35%, about 12% toabout 55%, about 12% to about 40%, about 12% to about 35%, about 15% toabout 55%, about 15% to about 40%, about 15% to about 35%, about 10%,about 12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about 25%,about 27.5%, about 30%, about 32.5%, about 35%, about 37.5%, about 40%,about 42.5%, about 45%, about 47.5%, about 50%, about 52.5% or about 55%(w/w). In some embodiments, the carrier system comprises one or morealcohols or glycols, or any combinations thereof, in an amount fromabout 25% to about 40% (w/w). In some embodiments, the carrier systemcomprises one or more alcohols or glycols, or any combinations thereof,in an amount of about 30% (w/w). In some embodiments, the alcohol isethanol or contains ethanol. In some preferred embodiments, the glycolsexclude glycol polymers. In some preferred embodiments, the glycolsexclude glycol polymers having an average molecular weight of greaterthan 200. In some embodiments, the glycols exclude polyethylene glycolhaving an average molecular weight of greater than about 200.

In some embodiments, the carrier system comprises one or more alcoholsor glycols, or any combinations thereof, in an amount from about 15% toabout 55% (w/w). In some embodiments, the carrier system comprises oneor more alcohols or glycols, or any combinations thereof, in an amountfrom about 25% to about 40% (w/w). In some embodiments, the carriersystem comprises one or more alcohols or glycols, or any combinationsthereof, in an amount of about 30% (w/w).

In some embodiments, the composition comprises at least one additionalingredient selected from the group consisting of: active pharmaceuticalingredients; enhancers; excipients; and agents used to adjust the pH,buffer the composition, prevent degradation, and improve appearance,odor, or taste.

In some embodiments, the compositions comprise at least one alkylglycoside. In some embodiments, the at least one alkyl glycoside is onedescribed in U.S. Pat. No. 5,661,130, which is incorporated by referenceherein.

In some embodiments, the composition comprises a benzodiazepine drugthat is fully dissolved in a solvent comprising a natural or synthetictocopherol or tocotrienol, and an alcohol or glycol. In someembodiments, the composition comprises a benzodiazepine drug that isfully dissolved in a solvent comprising a natural or synthetictocopherol or tocotrienol and an alcohol or glycol, wherein the solutionis at least substantially free of water. (In some embodiments,“substantially free of water” indicates that the solution contains lessthan about 1%, less than about 0.5%, less than about 0.25% or less thanabout 0.1% water.) In some embodiments, the composition consistsessentially of a benzodiazepine drug that is fully dissolved in asolvent consisting of one or more natural or synthetic tocopherols ortocotrienols, one or more alcohols or glycols, and optionally one ormore alkyl glycosides. In some embodiments, the composition consistsessentially of a benzodiazepine drug that is fully dissolved in asolvent consisting of one or more natural or synthetic tocopherols ortocotrienols, one or more alcohols or glycols, and optionally one ormore alkyl glycosides wherein the solution is at least substantiallyfree of water. (In some embodiments, “substantially free of water”indicates that the solution contains less than about 1%, less than about0.5%, less than about 0.25% or less than about 0.1% water.) In someembodiments, the composition consists of a benzodiazepine dissolved in asolvent consisting of one or more natural or synthetic tocopherols ortocotrienols, one or more alcohols or glycols, and optionally one ormore alkyl glycosides. In some embodiments, the composition consists ofa benzodiazepine dissolved in a solvent consisting of one or morenatural or synthetic tocopherols or tocotrienols, one or more alcoholsor glycols, and optionally one or more alkyl glycosides, wherein thesolution is at least substantially free of water. (In some embodiments,“substantially free of water” indicates that the solution contains lessthan about 1%, less than about 0.5%, less than about 0.25% or less thanabout 0.1% water.)

In some embodiments, the composition comprises a benzodiazepine drugthat is fully dissolved in a solvent comprising a natural or synthetictocopherol or tocotrienol, and an alcohol or glycol. Thus, in someembodiments, the composition is substantially free of benzodiazepinemicroparticles, nanoparticles or combinations thereof. In someembodiments, the composition comprises a benzodiazepine drug that isfully dissolved in a solvent comprising a natural or synthetictocopherol or tocotrienol and an alcohol or glycol, wherein the solutionis at least substantially free of water. (In some embodiments,“substantially free of water” indicates that the solution contains lessthan about 1%, less than about 0.5%, less than about 0.25% or less thanabout 0.1% water.) In some embodiments, the composition consistsessentially of a benzodiazepine drug that is fully dissolved in asolvent consisting of one or more natural or synthetic tocopherols ortocotrienols, one or more alcohols or glycols, and optionally one ormore alkyl glycosides. In some embodiments, the composition consistsessentially of a benzodiazepine drug that is fully dissolved in asolvent consisting of one or more natural or synthetic tocopherols ortocotrienols, one or more alcohols or glycols, and optionally one ormore alkyl glycosides wherein the solution is at least substantiallyfree of water. (In some embodiments, “substantially free of water”indicates that the solution contains less than about 1%, less than about0.5%, less than about 0.25% or less than about 0.1% water.) In someembodiments, the composition consists of a benzodiazepine dissolved in asolvent consisting of one or more natural or synthetic tocopherols, oneor more alcohols or glycols, and optionally one or more alkylglycosides. In some embodiments, the composition consists of abenzodiazepine dissolved in a solvent consisting of one or more naturalor synthetic tocopherols, one or more alcohols or glycols, andoptionally one or more alkyl glycosides, wherein the solution is atleast substantially free of water. (In some embodiments, “substantiallyfree of water” indicates that the solution contains less than about 1%,less than about 0.5%, less than about 0.25% or less than about 0.1%water.)

In some embodiments, the composition contains a benzodiazepine drug thatat least partially in a particulate form suspended in a carrier systemcontaining a natural or synthetic tocopherol or tocotrienol and one ormore alcohols or glycols. In some embodiments, substantially all thebenzodiazepine drug is in a particulate form. In some embodiments, atleast part of the benzodiazepine drug is in a microparticulate ornanoparticulate form. The carrier system is one in which the amount ofat least one benzodiazepine present in the composition exceeds itssolubility in the carrier system. In some embodiments, a carrier systemin such a composition includes water. In some embodiments, such a liquidcarrier system contains water and one or more excipients. In someembodiments, one or more excipients are dissolved or suspended in thecarrier system. In some embodiments, at least one such excipientstabilizes the suspension of benzodiazepine particulates in the carriersystem. In some embodiments, the carrier system may contain varyingconcentrations of parabens (e.g. methylparaben, propylparaben, etc.),and/or varying amounts of one or more surfactants, such as povidone(polyvinyl pyrrolidinone). In some embodiments, benzodiazepineparticulate suspensions specifically exclude one or more polymericglycols, such as polyethylene glycol. In some embodiments,benzodiazepine particulate suspensions specifically exclude one or morepolymeric glycols having a molecular weight greater than about 200g/mol. In some embodiments, the composition comprises a benzodiazepinedrug in a form including benzodiazepine microparticles and/ornanoparticles suspended in a carrier system comprising synthetictocopherol, one or more parabens, one or more alcohols or glycols, oneor more surfactants and water. In some embodiments, the compositioncomprises a benzodiazepine drug in a form including benzodiazepinemicroparticles or nanoparticles suspended in a carrier system comprisingVitamin E TPGS, one or both of methylparaben and propylparaben, at leastone glycol, povidone and water. In some embodiments, the compositioncomprises a benzodiazepine drug in a form including benzodiazepinemicroparticles and/or nanoparticles suspended in a carrier systemcomprising Vitamin E TPGS, methylparaben, propylparaben, propyleneglycol, povidone and water. In some embodiments, the compositionconsists essentially of a benzodiazepine drug in a form includingbenzodiazepine microparticles and/or nanoparticles suspended in acarrier system consisting essentially of a synthetic tocopherol, one ormore parabens, one or more alcohols or glycols, one or more surfactantsand water. In some embodiments, the composition consists essentially ofa benzodiazepine drug in a form including benzodiazepine microparticlesor nanoparticles suspended in a carrier system consisting essentially ofVitamin E TPGS, one or both of methylparaben and propylparaben, at leastone glycol, povidone and water. In some embodiments, the compositionconsists essentially of a benzodiazepine drug in a form includingbenzodiazepine microparticles and/or nanoparticles suspended in acarrier system consisting essentially of Vitamin E TPGS, methylparaben,propylparaben, propylene glycol, povidone and water. In someembodiments, the composition consists of a benzodiazepine drug in a formincluding benzodiazepine microparticles and/or nanoparticles suspendedin a carrier system consisting of a synthetic tocopherol, one or moreparabens, one or more alcohols or glycols, one or more surfactants andwater. In some embodiments, the composition consists of a benzodiazepinedrug in a form including benzodiazepine microparticles or nanoparticlessuspended in a carrier system consisting of Vitamin E TPGS, one or bothof methylparaben and propylparaben, at least one glycol, povidone andwater. In some embodiments, the composition consists of a benzodiazepinedrug in a form including benzodiazepine microparticles and/ornanoparticles suspended in a carrier system consisting of Vitamin ETPGS, methylparaben, propylparaben, propylene glycol, povidone andwater.

In some embodiments, the composition contains a benzodiazepine drug thatat least partially in a particulate form suspended in a carrier systemcontaining a natural or synthetic tocopherol or tocotrienol, one or morealcohols or glycols, and an alkyl glycoside. In some embodiments,substantially all the benzodiazepine drug is in a particulate form. Insome embodiments, at least part of the benzodiazepine drug is in amicroparticulate or nanoparticulate form. The carrier system is one inwhich the amount of at least one benzodiazepine present in thecomposition exceeds its solubility in the carrier system. In someembodiments, a carrier system in such a composition includes water. Insome embodiments, such a liquid carrier system contains water and one ormore excipients. In some embodiments, one or more excipients aredissolved or suspended in the carrier system. In some embodiments, atleast one such excipient stabilizes the suspension of benzodiazepineparticulates in the carrier system. In some embodiments, the carriersystem may contain varying concentrations of parabens (e.g.methylparaben, propylparaben, etc.), and/or varying amounts of one ormore surfactants, such as povidone (polyvinyl pyrrolidinone). In someembodiments, benzodiazepine particulate suspensions specifically excludeone or more polymeric glycols, such as polyethylene glycol. In someembodiments, benzodiazepine particulate suspensions specifically excludeone or more polymeric glycols having a molecular weight greater thanabout 200 g/mol. In some embodiments, the composition comprises abenzodiazepine drug in a form including benzodiazepine microparticlesand/or nanoparticles suspended in a carrier system comprising asynthetic tocopherol, one or more parabens, one or more alcohols orglycols, an alkyglycoside and water. In some embodiments, thecomposition comprises a benzodiazepine drug in a form includingbenzodiazepine microparticles or nanoparticles suspended in a carriersystem comprising Vitamin E TPGS, one or both of methylparaben andpropylparaben, at least one glycol, an alkyl glycoside and water. Insome embodiments, the composition comprises a benzodiazepine drug in aform including benzodiazepine microparticles and/or nanoparticlessuspended in a carrier system comprising Vitamin E TPGS, methylparaben,propylparaben, propylene glycol, an alkyl glycoside and water. In someembodiments, the composition consists essentially of a benzodiazepinedrug in a form including benzodiazepine microparticles and/ornanoparticles suspended in a carrier system consisting essentially of asynthetic tocopherol, one or more parabens, one or more alcohols orglycols, an alkyl glycoside, optionally a surfactant, and water. In someembodiments, the composition consists essentially of a benzodiazepinedrug in a form including benzodiazepine microparticles or nanoparticlessuspended in a carrier system consisting essentially of Vitamin E TPGS,one or both of methylparaben and propylparaben, at least one glycol, analkyl glycoside, optionally a povidone and water. In some embodiments,the composition consists essentially of a benzodiazepine drug in a formincluding benzodiazepine microparticles and/or nanoparticles suspendedin a carrier system consisting essentially of Vitamin E TPGS,methylparaben, propylparaben, propylene glycol, an alkyl glycoside,optionally a povidone, and water. In some embodiments, the compositionconsists of a benzodiazepine drug in a form including benzodiazepinemicroparticles and/or nanoparticles suspended in a carrier systemconsisting of a synthetic tocopherol, one or more parabens, one or morealcohols or glycols, an alkyl glycoside, optionally one or moresurfactants, and water. In some embodiments, the composition consists ofa benzodiazepine drug in a form including benzodiazepine microparticlesor nanoparticles suspended in a carrier system consisting of Vitamin ETPGS, one or both of methylparaben and propylparaben, at least oneglycol, an alkyl glycoside, optionally a povidone and water. In someembodiments, the composition consists of a benzodiazepine drug in a formincluding benzodiazepine microparticles and/or nanoparticles suspendedin a carrier system consisting of Vitamin E TPGS, methylparaben,propylparaben, propylene glycol, an alkyl glycoside, optionally apovidone and water.

The invention also discloses a method of treating a patient with adisorder that may be treatable with a benzodiazepine drug. In someembodiments, the patient is a human. In some embodiments, the methodcomprises: administering to one or more nasal mucosal membranes of apatient a pharmaceutical composition for nasal administration comprisinga benzodiazepine drug; one or more natural or synthetic tocopherols ortocotrienols, or any combinations thereof, in an amount from about 30%to about 95% (w/w); and one or more alcohols or glycols, or anycombinations thereof, in an amount from about 5% to about 70% (w/w),preferably about 10% to about 70% (w/w). In some embodiments, thebenzodiazepine is dissolved in the one or more natural or synthetictocopherols or tocotrienols, or any combinations thereof, in an amountfrom about 30% to about 95% (w/w); and the one or more alcohols orglycols, or any combinations thereof, in an amount from about 5% toabout 70% (w/w), preferably about 10% to about 70% (w/w). In someembodiments, the benzodiazepine drug is dissolved in a carrier system.In other embodiments, at least part of the benzodiazepine drug is in aform including microparticles, nanoparticles, or combinations thereof.In some embodiments, the composition is substantially free ofbenzodiazepine microparticles, nanoparticles or combinations thereof.

In some embodiments, the benzodiazepine drug is selected from the groupconsisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam,clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam,halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam,lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, or anypharmaceutically-acceptable salts thereof, and any combinations thereof.In some embodiments, the benzodiazepine drug is diazepam, or apharmaceutically-acceptable salt thereof. In some embodiments, thebenzodiazepine drug comprises benzodiazepine microparticles,nanoparticles, or combinations thereof. In some embodiments, thebenzodiazepine nanoparticles have an effective average particle size ofless than about 5000 nm.

In some embodiments, the one or more natural or synthetic tocopherols ortocotrienols are selected from the group consisting of: α-tocopherol,β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol,γ-tocotrienol, δ-tocotrienol, tocophersolan, any isomers thereof, anyesters thereof, any analogs or derivatives thereof, and any combinationsthereof. A synthetic tocopherol may include a tocopherol that has beenmodified to include a hydrophilic group, such as a polyethylene glycolgroup, which may be directly covalently bonded to the tocopherol or maybe linked to the tocopherol through a covalent linking group, such as adiacid. An exemplary synthetic tocopherol of this type is Vitamin EPolyethylene Glycol Succinate (Vitamin E TPGS), although the personskilled in the art will be able to envision other synthetic tocopherolsthat have similar diacid and/or hydrophilic groups.

In some embodiments, the one or more alcohols are selected from thegroup consisting of: ethanol, propyl alcohol, butyl alcohol, pentanol,benzyl alcohol, any isomers thereof, and any combinations thereof. Insome embodiments, the one or more glycols are selected from the groupconsisting of: ethylene glycol, propylene glycol, butylene glycol,pentylene glycol, any isomers thereof, and any combinations thereof. Insome embodiments, one or more glycols specifically excludes polymericglycols, such as polyethylene glycol. In some embodiments, one or moreglycols specifically excludes a polymeric glycol having a molecularweight of greater than about 200 g/mol.

In some embodiments, the benzodiazepine drug is present in the carriersystem in a concentration from about 1 mg/mL to about 600 mg/mL. In someembodiments, the benzodiazepine drug is present in the carrier system ina concentration of from about 10 mg/mL to about 250 mg/mL. In someembodiments, the benzodiazepine drug is present in the carrier system ina concentration of from about 20 mg/mL to about 50 mg/mL.

In some embodiments, the carrier system comprises one or more natural orsynthetic tocopherols or tocotrienols, or any combinations thereof, inan amount from about 45% to about 85% (w/w). In some embodiments, thecarrier system comprises one or more natural or synthetic tocopherols ortocotrienols, or any combinations thereof, in an amount from about 60%to about 75% (w/w). In some embodiments, the carrier system comprisesone or more natural or synthetic tocopherols or tocotrienols, or anycombinations thereof, in an amount of about 70% (w/w). In someembodiments, especially where particulate suspensions of abenzodiazepine drug are contemplated, the compositions may include atocopherol, especially a synthetic tocopherol having a hydrophilic groupcovalently linked to a tocopherol. In other embodiments, especiallywhere a solution of benzodiazepine drug is contemplated, the tocopherolis substantially or completely free of Vitamin E TPGS.

In some embodiments, the carrier system comprises one or more alcoholsor glycols, or any combinations thereof, in an amount from about 10% toabout 55% (w/w). In some embodiments, the carrier system comprises oneor more alcohols or glycols, or any combinations thereof, in an amountfrom about 25% to about 40% (w/w). In some embodiments, the carriersystem comprises one or more alcohols or glycols, or any combinationsthereof, in an amount from about 30% (w/w). In some embodiments theamount of one or more alcohols or glycols in the carrier system is about10% to about 55%, about 10% to about 40%, about 10% to about 35%, about12% to about 55%, about 12% to about 40%, about 12% to about 35%, about15% to about 55%, about 15% to about 40%, about 15% to about 35%, about10%, about 12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about25%, about 27.5%, about 30%, about 32.5%, about 35%, about 37.5%, about40%, about 42.5%, about 45%, about 47.5%, about 50%, about 52.5% orabout 55% (w/w).

In some embodiments, the composition comprises at least one additionalingredient selected from the group consisting of: active pharmaceuticalingredients; enhancers; excipients; and agents used to adjust the pH,buffer the composition, prevent degradation, and improve appearance,odor, or taste.

In some embodiments, a composition comprises at least one penetrationenhancer in addition to a benzodiazepine drug, a natural or synthetictocopherol or tocotrienol, and an alcohol or glycol. In someembodiments, the penetration enhancer is an alkyl glycoside. In someembodiments, the alkyl glycoside refers to any sugar joined to anyhydrophobic alkyl, as described in U.S. Pat. No. 5,661,130, which isincorporated herein by reference in its entirety. The hydrophobic alkylcan be any suitable length, for example about 9 to about 24 carbons inlength, especially about 10 to about 14 carbons in length. Thehydrophobic alkyl can be branched and/or partially or whollyunsaturated. The alkyl may be joined to the saccharide core for examplethrough a carbonyl group, whereby an ester group may be formed. Asuitable alkyl glycoside will have the characteristics of beingnontoxic, nonionic, and capable of increasing the absorption of abenzodiazepine drug when it is administered intranasally as describedherein. Exemplary saccharides that may be covalently joined to an alkylaccording to the present invention include glucose, maltose,maltotriose, maltotetrose, sucrose and trehalose. Exemplary alkylglycosides that may be employed include octyl-, nonyl-, decyl-,undecyl-, dodecyl, tridecyl, tetradecyl, pentadecyl, octadecyl α- orβ-D-maltoside, -glucoside or sucroside. In some embodiments, thepreferred glycosides include maltose, sucrose or glucose linked byglycosidic linkage to an alkyl chain of 9, 10, 12, 14, 16, 18 or 20carbon atoms. Where present, the amount of alkyl glycoside in thecomposition is sufficient to enhance the absorption of a benzodiazepinedrug administered by the intranasal route. In some embodiments, theamount of alkyl glycoside in the composition is selected so as toenhance absorption of the benzodiazepine drug, while at the same timenot significantly irritating the nasal mucosa. In some embodiments, theamount of alkyl glycoside in the composition is in a range of about0.01% (w/v) to about 1% (w/v). In some embodiments, the amount of alkylglycoside in the composition is in a range of about 0.05% (w/v) to about0.5% (w/v), or about 0.125% (w/v) to about 0.5% (w/v).

In some embodiments, the composition is in a pharmaceutically-acceptablespray formulation, and further comprising administering the compositionto one or more nasal mucosal membranes of the patient. In someembodiments, the therapeutically effective amount is from about 1 mg toabout 20 mg of the benzodiazepine. In some embodiments, thepharmaceutical composition is in a pharmaceutically-acceptable sprayformulation having volume from about 100_, to 200 μL.

In some embodiments, the administration of the composition comprisesspraying at least a portion of the therapeutically effective amount ofthe composition into at least one nostril. In some embodiments, theadministration of the composition comprises spraying at least a portionof the therapeutically effective amount of the composition into eachnostril. In some embodiments, the administration of the compositioncomprises spraying a first quantity of the composition into the firstnostril, spraying a second quantity of the composition into a secondnostril, and optionally after a pre-selected time delay, spraying athird quantity of the composition into the first nostril. Someembodiments further comprise, optionally after a pre-selected timedelay, administering at least a fourth quantity of the composition tothe second nostril.

In some embodiments, the administration of the composition begins at anytime before or after onset of symptoms of a disorder which may betreatable with the composition.

DEFINITIONS

As used herein the phrase “therapeutically effective amount” (or moresimply “effective amount”) includes an amount sufficient to provide aspecific therapeutic response for which the drug is administered to apatient in need of particular treatment. The skilled clinician willrecognize that the therapeutically effective amount of drug will dependupon the patient, the indication and the particular drug administered.

As used herein, the modifier “about” is intended to have its regularlyrecognized meaning of approximately. In some embodiments, the term maybe more precisely interpreted as meaning within a particular percentageof the modified value, e.g. “about” may in some embodiments mean±20%,±10%, ±5%, ±2%, or ±1% or less.

As used herein, the phrase “analogs or derivatives” includes moleculesthat differ from one another molecule due to one or more atoms orfunctional groups having been replaced with a different atom orfunctional group. This may result in molecules with similar chemicalformulas but different chemical and/or biological properties.

As used herein, the term, “isomer” includes molecules with identicalchemical formulas, but between which the arrangement of the moleculesmay vary. These varying arrangements may result in molecules withidentical chemical formulas but different chemical properties. By way ofnon-limiting example, propanol has the chemical formula C₃H₇OH. It maybe found as propan-1-ol, wherein the —OH is found attached to an endcarbon. Alternatively, it may be found as propan-2-ol, wherein the —OHis found attached to the second carbon.

As used herein, the term “seizure” includes commonly recognized types ofseizures, including absence seizures, myoclonic seizures, clonicseizures, tonic seizures, tonic-clonic seizures, and atonic seizures.Often seizures, particularly severe tonic or tonic-clonic seizures, willbe presaged by one or more aura that will be familiar to the patient orthose familiar with the patient. Each patient will generally experiencea different type of aura, which is unique to the patient; however aurasmay be classified as audible, visual, olfactory or tactile sensationsthat usually, or at least often, precedes a patient's experiencing aseizure. (Not all patients who suffer seizures experience aura; howeveraura are not uncommon amongst those who suffer the worst type ofseizures, especially tonic-clonic seizures.)

As used herein, the term “prevention” refers to a forestalling,including temporary forestalling, of the onset of a disorder. In thecase of seizures, this can occur either with or without the benefit of awarning aura.

As used herein, the term “treatment” refers to a reduction in theintensity and/or duration of a disorder, or similar effects. The termalso encompasses the side-effects of such a “treatment.”

As used herein, unless otherwise qualified, “a” and “an” can mean one ormore.

As used herein, the term “comprising” in all its variants, is atransitional phrase used in a claim to indicate that the inventionincludes or contains, but is not limited to, the specifically recitedclaim elements.

As used herein, the phrase “consisting essentially of” is a transitionalphrase used in a claim to indicate that the a following list ofingredients, parts or process steps must be present in the claimedcomposition, machine or process, but that the claim is open to unlistedingredients, parts or process steps that do not materially affect thebasic and novel properties of the invention.

As used herein, the term “consisting of” is a transitional phrase usedin a claim to indicate that the claimed invention includes only thoseelements set forth in the claim.

Benzodiazepine Drugs

In the context of the present invention, the term “benzodiazepine drug”includes any therapeutically effective benzodiazepine compound, orpharmaceutically acceptable salt, or combinations thereof. In someembodiments, benzodiazepine comprises a member of the group consistingof alprazolam, diazepam, flurazepam, lorazepam, medazepam, mexazolam,midazolam, temazepam and pharmaceutically acceptable salts andcombinations thereof.

It should be recognized by those of skill in the art that additionalbenzodiazepine compounds that have heretofore been considered to havemarginal or little therapeutic benefit, either because of lowbioavailability, poor pharmacokinetic properties or poor pharmacodynamicproperties, may find use through the present invention, which canprovide for improved bioavailability of benzodiazepine drugs, deliveryof higher concentrations of benzodiazepine drugs via the nasal route,faster attainment of therapeutic levels of benzodiazepine in the bloodplasma, avoidance of the liver portal vein and concomitant avoidance offirst pass effects and/or faster presentation of benzodiazepine drug tothe brain.

For example, most benzodiazepines are so slightly soluble in water thata therapeutically effective amount cannot be dissolved in a volume ofaqueous solvent that is amenable to application to a mucosal membrane.By use of the present carrier system, which in some embodiments,provides an improved ability to dissolve benzodiazepine drugs, thepresent invention allows benzodiazepine drugs to be administered to oneor more mucosal membranes, including to nasal mucosal membranes. Thiscan allow one to administer the drug without hospitalization orunnecessary discomfort. Additionally, in some embodiments of the presentinvention, such as nasal administration, the digestive system largelymay be bypassed. This latter improvement can yield improvedbioavailability, faster attainment of therapeutic levels ofbenzodiazepine in the blood plasma, avoidance of the liver portal vein,and/or concomitant avoidance of first pass effects.

Nasal administration of the composition can result in fasterpresentation of the one or more benzodiazepine drugs to the brain due tothe close proximity of the membranes and the brain. A seizing patient,for example, suffers from rigid muscles and uncontrollable movement.This can make oral and/or intravenous administration difficult orinconvenient. However, the nasal passageways remain open and easilyaccessible, and therefore is a useful route of administration for of thepresent invention.

In some embodiments, the pharmaceutical composition is used to treat apatient suffering from a disorder that is amenable to treatment orprevention with an effective amount of the one or more benzodiazepinedrugs. By way of non-limiting example such disorders can include:insomnia, anxiety, seizures, muscle spasms and rigidity, and thesymptoms of drug withdrawal.

In some embodiments, the one or more benzodiazepine drugs, are usedalone or in combination with another anticonvulsant drug to treatseizure, protect against seizure, reduce or ameliorate the intensity ofseizure, reduce or ameliorate the frequency of seizure, and/or preventoccurrence or re-occurrence of seizure.

Alprazolam(8-chloro-6-phenyl-1-methyl-4H-1,2,4-triazolo[4,3-a][1,4]benzodiazepine)

Alprazolam is a benzodiazepine drug having sedative, tranquilizing andmuscle relaxing properties. It is classified as an anxiolytic.Alprazolam has also been shown to be useful in the treatment of panicdisorder. The dosage of alprazolam varies by indication, however it isexpected that a therapeutic dose will be in the range of about 0.5 toabout 4, preferably about 1 to about 2 mg per dose, from 1 to 8,preferably from 2 to 8, and in some preferred embodiments about 4 toabout 6 times per day. Alprazolam may be manufactured using the processdisclosed in U.S. Pat. No. 3,987,052, which is incorporated herein byreference in its entirety.

In some embodiments, alprazolam is used alone or in combination withother drugs to provide an anxiolytic effect, an anticonvulsant effect, asedative effect, a skeletal muscle relaxant effect, an amnesic effect orcombinations of the foregoing effects.

In some embodiments, alprazolam is used alone or in combination withanother anticonvulsant drug to treat seizure, protect against seizure,reduce or ameliorate the intensity of seizure, reduce or ameliorate thefrequency of seizure, and/or prevent occurrence or re-occurrence ofseizure. Alprazolam may be administered by the patient or other person(such as a healthcare professional) while the patient is in anon-seizing state to protect against seizure. Even where protectionagainst seizure is not absolute, administration of alprazolam may reduceor ameliorate the intensity of seizure and/or reduce or ameliorate thefrequency of seizure. In some embodiments, administration of alprazolammay prevent occurrence of seizure. In some embodiments, especially wherethe patient is prone to experiencing serial seizures or statusepilepticus, administration of alprazolam may aid in interrupting theseizure cycle and may thus prevent the re-occurrence of seizure. Inaddition to the benzodiazepines (such as diazepam), otheranti-convulsant drugs may be combined with alprazolam to provide ananticonvulsant or synergistic anticonvulsant effect.

Alprazolam may also be administered by another person (e.g. anacquaintance or associate, a family member or a health careprofessional) to the patient while the patient is in a state of seizure.Thus, one of the advantages of the formulations according to the presentinvention is the ability to administer them in an acute therapeuticenvironment to treat the seizure victim, for example, nasally. Among thebeneficial therapeutic effects that may be imparted by acute dosing ofbenzodiazepine anticonvulsants, such as nasal dosing, are: reduction inthe severity of the seizure (e.g. general relaxation of the muscles,reduction in seizure-induced anxiety experienced by the patient and ageneral impartation of a feeling of well-being to the patient),reduction in the duration of the seizure, reduction in the probabilitythat the patient will experience a repeat seizure, an increase in theinterval between the current seizure and the next seizure. Thus, thealprazolam formulations of the invention, and in particular nasalformulations, provide fast onset of therapeutic benefit—in someinstances less than about 30 minutes, less than about 15 minutes, lessthan about 10 minutes, and in some cases less than about 5 minutes. Thealprazolam formulations of the invention, and in particular nasalformulations, also provide convenient administration of atherapeutically beneficial drug to a patient that does not requireintravenous drug administration or rectal drug administration.

Often seizures, particularly severe tonic or tonic-clonic seizures, willbe presaged by one or more aura events that will be familiar to thepatient or those familiar with the patient. These auras are practicallysui generis for each patient, but may be classified as audible, visual,olfactory or tactile sensations that usually, or typically, precedes apatient's experiencing a seizure. In some embodiments of the invention,the method includes prompt administration of a preparation of abenzodiazepine drug according to the invention during the aura. In someembodiments, such intra-aural administration of benzodiazepine drug, forexample by nasal administration, will prevent or at least ameliorate theeffects (intensity, duration or both) of the impending seizure. Thus, inthe context of this invention, prevention of seizure refers to atemporary forestalling of the onset of seizure, either with or withoutthe benefit of a warning aura.

Diazepam(7-chloro-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one)

Diazepam is a benzodiazepine drug having sedative, tranquilizing andmuscle relaxing properties. It is classified as an anxiolytic andskeletal muscle relaxant. It possesses anxiolytic, anticonvulsant,sedative, skeletal muscle relaxant and amnesic properties. The dosage ofdiazepam may vary by indication, however it is expected that atherapeutic dose will be in the range of about 1 to about 20, preferablyabout 2 to about 10 mg per dose, from 1 to 8, preferably from 2 to 8,and in some preferred embodiments about 4 to about 6 times per day.Diazepam may be manufactured using the process disclosed in one of U.S.Pat. No. 3,371,085; 3,109,843; 3,136,815 or 3,102,116, each of which isincorporated herein by reference in its entirety.

In some embodiments, diazepam is used alone or in combination with otherdrugs to provide an anxiolytic effect, an anticonvulsant effect, asedative effect, a skeletal muscle relaxant effect, an amnesic effect orcombinations of the foregoing effects.

In some embodiments, diazepam is used alone or in combination withanother anticonvulsant drug to treat seizure, protect against seizure,reduce or ameliorate the intensity of seizure, reduce or ameliorate thefrequency of seizure, and/or prevent occurrence or re-occurrence ofseizure. Diazepam may be administered by the patient or other person(such as a healthcare professional) while the patient is in anon-seizing state to protect against seizure. Even where protectionagainst seizure is not absolute, administration of diazepam may reduceor ameliorate the intensity of seizure and/or reduce or ameliorate thefrequency of seizure. In some embodiments, administration of diazepammay prevent occurrence of seizure. In some embodiments, especially wherethe patient is prone to experiencing serial seizures or statusepilepticus, administration of diazepam may aid in interrupting theseizure cycle and may thus prevent the re-occurrence of seizure. Inaddition to the benzodiazepines (such as diazepam), otheranti-convulsant drugs may be combined with diazepam to provide asynergistic anticonvulsant effect.

Diazepam may also be administered by another person (e.g. anacquaintance or associate, a family member or a health careprofessional) to the patient while the patient is in a state of seizure.Thus, one of the advantages of the formulations according to the presentinvention is the ability to administer them in an acute therapeuticenvironment to treat the seizure victim, for example, nasally. Among thebeneficial therapeutic effects that may be imparted by acute dosing ofbenzodiazepine anticonvulsants, such as nasal dosing, are: reduction inthe severity of the seizure (e.g. general relaxation of the muscles,reduction in seizure-induced anxiety experienced by the patient and ageneral impartation of a feeling of well-being to the patient),reduction in the duration of the seizure, reduction in the probabilitythat the patient will experience a repeat seizure, an increase in theinterval between the current seizure and the next seizure. Thus, thediazepam formulations of the invention, and in particular nasalformulations, provide fast onset of therapeutic benefit—in someinstances less than about 30 minutes, less than about 15 minutes, lessthan about 10 minutes, and in some cases less than about 5 minutes. Thediazepam formulations of the invention, and in particular nasalformulations, also provide convenient administration of atherapeutically beneficial drug to a patient that does not requireintravenous drug administration or rectal drug administration.

Often seizures, particularly severe tonic or tonic-clonic seizures, willbe presaged by one or more aura events that will be familiar to thepatient or those familiar with the patient. These auras are practicallysui generis for each patient, but may be classified as audible, visual,olfactory or tactile sensations that usually, or typically, precedes apatient's experiencing a seizure. In some embodiments of the invention,the method includes prompt administration of a preparation of abenzodiazepine drug according to the invention during the aura. In someembodiments, such intra-aural administration of benzodiazepine drug, forexample by nasal administration, will prevent or at least ameliorate theeffects (intensity, duration or both) of the impending seizure. Thus, inthe context of this invention, prevention of seizure refers to atemporary forestalling of the onset of seizure, either with or withoutthe benefit of a warning aura.

Flurazepam(7-chloro-5-(2-flurophenyl)-2,3-dihydro-1-(2-(diethylamino)ethyl)-1H-1,4-benzodiazepin-2-one)

Flurazepam is a benzodiazepine drug having sedative (especiallysoporific and hypnotic), anxiolytic, anticonvulsant and muscle relaxingproperties. It is classified as an sedative, hypnotic. Flurazepam hasbeen shown to be useful in the treatment of insomnia. The dosage offlurazepam varies by indication, however it is expected that atherapeutic dose will be in the range of about 5 to 40, preferably about20 to about 35 mg per dose, from 1 to 8, preferably from 2 to 8, and insome preferred embodiments about 4 to about 6 times per day. Flurazepammay be manufactured using the process disclosed in U.S. Pat. No.3,567,710 or 3,299,053, each of which is incorporated herein byreference in its entirety.

In some embodiments, flurazepam is used alone or in combination withother drugs to provide an anxiolytic effect, an anticonvulsant effect, asedative effect, a skeletal muscle relaxant effect, an amnesic effect orcombinations of the foregoing effects.

In some embodiments, flurazepam is used alone or in combination withanother anticonvulsant drug to treat seizure, protect against seizure,reduce or ameliorate the intensity of seizure, reduce or ameliorate thefrequency of seizure, and/or prevent occurrence or re-occurrence ofseizure. Flurazepam may be administered by the patient or other person(such as a healthcare professional) while the patient is in anon-seizing state to protect against seizure. Even where protectionagainst seizure is not absolute, administration of flurazepam may reduceor ameliorate the intensity of seizure and/or reduce or ameliorate thefrequency of seizure. In some embodiments, administration of flurazepammay prevent occurrence of seizure. In some embodiments, especially wherethe patient is prone to experiencing serial seizures or statusepilepticus, administration of flurazepam may aid in interrupting theseizure cycle and may thus prevent the re-occurrence of seizure. Inaddition to the benzodiazepines (such as diazepam), otheranti-convulsant drugs may be combined with flurazepam to provide asynergistic anticonvulsant effect.

Flurazepam may also be administered by another person (e.g. anacquaintance or associate, a family member or a health careprofessional) to the patient while the patient is in a state of seizure.Thus, one of the advantages of the formulations according to the presentinvention is the ability to administer them in an acute therapeuticenvironment to treat the seizure victim, for example, nasally. Among thebeneficial therapeutic effects that may be imparted by acute dosing ofbenzodiazepine anticonvulsants, such as nasal dosing, are: reduction inthe severity of the seizure (e.g. general relaxation of the muscles,reduction in seizure-induced anxiety experienced by the patient and ageneral impartation of a feeling of well-being to the patient),reduction in the duration of the seizure, reduction in the probabilitythat the patient will experience a repeat seizure, an increase in theinterval between the current seizure and the next seizure. Thus, theflurazepam formulations of the invention, and in particular nasalformulations, provide fast onset of therapeutic benefit—in someinstances less than about 30 minutes, less than about 15 minutes, lessthan about 10 minutes, and in some cases less than about 5 minutes. Theflurazepam formulations of the invention, and in particular nasalformulations, also provide convenient administration of atherapeutically beneficial drug to a patient that does not requireintravenous drug administration or rectal drug administration.

Often seizures, particularly severe tonic or tonic-clonic seizures, willbe presaged by one or more aura events that will be familiar to thepatient or those familiar with the patient. These auras are practicallysui generis for each patient, but may be classified as audible, visual,olfactory or tactile sensations that usually, or typically, precedes apatient's experiencing a seizure. In some embodiments of the invention,the method includes prompt administration of a preparation of abenzodiazepine drug according to the invention during the aura. In someembodiments, such intra-aural administration of benzodiazepine drug, forexample by nasal administration, will prevent or at least ameliorate theeffects (intensity, duration or both) of the impending seizure. Thus, inthe context of this invention, prevention of seizure refers to atemporary forestalling of the onset of seizure, either with or withoutthe benefit of a warning aura.

Lorazepam(7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one)

Lorazepam is a benzodiazepine drug having sedative, tranquilizing,anticonvulsant, amnesic and muscle relaxing properties. It is classifiedas an anxiolytic. Lorazepam has also been shown to be useful in thetreatment of nausea. The dosage of lorazepam varies by indication,however it is expected that a therapeutic dose will be in the range ofabout 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from1 to 8, preferably from 2 to 8, and in some preferred embodiments about4 to about 6 times per day. Lorazepam may be manufactured using theprocess disclosed in U.S. Pat. No. 3,296,249, which is incorporatedherein by reference in its entirety.

In some embodiments, lorazepam is used alone or in combination withother drugs to provide an anxiolytic effect, an anticonvulsant effect, asedative effect, a skeletal muscle relaxant effect, an amnesic effect orcombinations of the foregoing effects.

In some embodiments, lorazepam is used alone or in combination withanother anticonvulsant drug to treat seizure, protect against seizure,reduce or ameliorate the intensity of seizure, reduce or ameliorate thefrequency of seizure, and/or prevent occurrence or re-occurrence ofseizure. Lorazepam may be administered by the patient or other person(such as a healthcare professional) while the patient is in anon-seizing state to protect against seizure. Even where protectionagainst seizure is not absolute, administration of lorazepam may reduceor ameliorate the intensity of seizure and/or reduce or ameliorate thefrequency of seizure. In some embodiments, administration of lorazepammay prevent occurrence of seizure. In some embodiments, especially wherethe patient is prone to experiencing serial seizures or statusepilepticus, administration of lorazepam may aid in interrupting theseizure cycle and may thus prevent the re-occurrence of seizure. Inaddition to the benzodiazepines (such as diazepam), otheranti-convulsant drugs may be combined with lorazepam to provide asynergistic anticonvulsant effect.

Lorazepam may also be administered by another person (e.g. anacquaintance or associate, a family member or a health careprofessional) to the patient while the patient is in a state of seizure.Thus, one of the advantages of the formulations according to the presentinvention is the ability to administer them in an acute therapeuticenvironment to treat the seizure victim, for example, nasally. Among thebeneficial therapeutic effects that may be imparted by acute dosing ofbenzodiazepine anticonvulsants, such as nasal dosing, are: reduction inthe severity of the seizure (e.g. general relaxation of the muscles,reduction in seizure-induced anxiety experienced by the patient and ageneral impartation of a feeling of well-being to the patient),reduction in the duration of the seizure, reduction in the probabilitythat the patient will experience a repeat seizure, an increase in theinterval between the current seizure and the next seizure. Thus, thelorazepam formulations of the invention, and in particular nasalformulations, provide fast onset of therapeutic benefit—in someinstances less than about 30 minutes, less than about 15 minutes, lessthan about 10 minutes, and in some cases less than about 5 minutes. Thelorazepam formulations of the invention, and in particular nasalformulations, also provide convenient administration of atherapeutically beneficial drug to a patient that does not requireintravenous drug administration or rectal drug administration.

Often seizures, particularly severe tonic or tonic-clonic seizures, willbe presaged by one or more aura events that will be familiar to thepatient or those familiar with the patient. These auras are practicallysui generis for each patient, but may be classified as audible, visual,olfactory or tactile sensations that usually, or typically, precedes apatient's experiencing a seizure. In some embodiments of the invention,the method includes prompt administration of a preparation of abenzodiazepine drug according to the invention during the aura. In someembodiments, such intra-aural administration of benzodiazepine drug, forexample by nasal administration, will prevent or at least ameliorate theeffects (intensity, duration or both) of the impending seizure. Thus, inthe context of this invention, prevention of seizure refers to atemporary forestalling of the onset of seizure, either with or withoutthe benefit of a warning aura.

Medazepam((7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine)

Medazepam is a benzodiazepine drug having sedative, tranquilizing,anticonvulsant, amnesic and muscle relaxing properties. It is classifiedas an anxiolytic. Medazepam has also been shown to be useful in thetreatment of nausea. The dosage of medazepam varies by indication,however it is expected that a therapeutic dose will be in the range ofabout 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from1 to 8, preferably from 2 to 8, and in some preferred embodiments about4 to about 6 times per day. Medazepam may be manufactured using theprocess disclosed in U.S. Pat. No. 3,243,427, which is incorporatedherein by reference in its entirety.

In some embodiments, medazepam is used alone or in combination withother drugs to provide an anxiolytic effect, an anticonvulsant effect, asedative effect, a skeletal muscle relaxant effect, an amnesic effect orcombinations of the foregoing effects.

In some embodiments, medazepam is used alone or in combination withanother anticonvulsant drug to treat seizure, protect against seizure,reduce or ameliorate the intensity of seizure, reduce or ameliorate thefrequency of seizure, and/or prevent occurrence or re-occurrence ofseizure. Medazepam may be administered by the patient or other person(such as a healthcare professional) while the patient is in anon-seizing state to protect against seizure. Even where protectionagainst seizure is not absolute, administration of medazepam may reduceor ameliorate the intensity of seizure and/or reduce or ameliorate thefrequency of seizure. In some embodiments, administration of medazepammay prevent occurrence of seizure. In some embodiments, especially wherethe patient is prone to experiencing serial seizures or statusepilepticus, administration of medazepam may aid in interrupting theseizure cycle and may thus prevent the re-occurrence of seizure. Inaddition to the benzodiazepines (such as diazepam), otheranti-convulsant drugs may be combined with medazepam to provide asynergistic anticonvulsant effect.

Medazepam may also be administered by another person (e.g. anacquaintance or associate, a family member or a health careprofessional) to the patient while the patient is in a state of seizure.Thus, one of the advantages of the formulations according to the presentinvention is the ability to administer them in an acute therapeuticenvironment to treat the seizure victim, for example, nasally. Among thebeneficial therapeutic effects that may be imparted by acute dosing ofbenzodiazepine anticonvulsants, such as nasal dosing, are: reduction inthe severity of the seizure (e.g. general relaxation of the muscles,reduction in seizure-induced anxiety experienced by the patient and ageneral impartation of a feeling of well-being to the patient),reduction in the duration of the seizure, reduction in the probabilitythat the patient will experience a repeat seizure, an increase in theinterval between the current seizure and the next seizure. Thus, themedazepam formulations of the invention, and in particular nasalformulations, provide fast onset of therapeutic benefit—in someinstances less than about 30 minutes, less than about 15 minutes, lessthan about 10 minutes, and in some cases less than about 5 minutes. Themedazepam formulations of the invention, and in particular nasalformulations, also provide convenient administration of atherapeutically beneficial drug to a patient that does not requireintravenous drug administration or rectal drug administration.

Often seizures, particularly severe tonic or tonic-clonic seizures, willbe presaged by one or more aura events that will be familiar to thepatient or those familiar with the patient. These auras are practicallysui generis for each patient, but may be classified as audible, visual,olfactory or tactile sensations that usually, or typically, precedes apatient's experiencing a seizure. In some embodiments of the invention,the method includes prompt administration of a preparation of abenzodiazepine drug according to the invention during the aura. In someembodiments, such intra-aural administration of benzodiazepine drug, forexample by nasal administration, will prevent or at least ameliorate theeffects (intensity, duration or both) of the impending seizure. Thus, inthe context of this invention, prevention of seizure refers to atemporary forestalling of the onset of seizure, either with or withoutthe benefit of a warning aura.

Mexazolam(10-Chloro-11b-(2-chlorophenyl)-1,3,7,11b-tetrahydro-3-methyloxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one)

Mexazolam is a benzodiazepine drug having sedative, tranquilizing,anticonvulsant, amnesic and muscle relaxing properties. It is classifiedas an anxiolytic. Mexazolam has also been shown to be useful in thetreatment of nausea. The dosage of mexazolam varies by indication,however it is expected that a therapeutic dose will be in the range ofabout 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from1 to 8, preferably from 2 to 8, and in some preferred embodiments about4 to about 6 times per day. Mexazolam may be manufactured using theprocess disclosed in U.S. Pat. No. 3,722,371, which is incorporatedherein by reference in its entirety.

In some embodiments, mexazolam is used alone or in combination withother drugs to provide an anxiolytic effect, an anticonvulsant effect, asedative effect, a skeletal muscle relaxant effect, an amnesic effect orcombinations of the foregoing effects.

In some embodiments, mexazolam is used alone or in combination withanother anticonvulsant drug to treat seizure, protect against seizure,reduce or ameliorate the intensity of seizure, reduce or ameliorate thefrequency of seizure, and/or prevent occurrence or re-occurrence ofseizure. Mexazolam may be administered by the patient or other person(such as a healthcare professional) while the patient is in anon-seizing state to protect against seizure. Even where protectionagainst seizure is not absolute, administration of mexazolam may reduceor ameliorate the intensity of seizure and/or reduce or ameliorate thefrequency of seizure. In some embodiments, administration of mexazolammay prevent occurrence of seizure. In some embodiments, especially wherethe patient is prone to experiencing serial seizures or statusepilepticus, administration of mexazolam may aid in interrupting theseizure cycle and may thus prevent the re-occurrence of seizure. Inaddition to the benzodiazepines (such as diazepam), otheranti-convulsant drugs may be combined with mexazolam to provide asynergistic anticonvulsant effect.

Mexazolam may also be administered by another person (e.g. anacquaintance or associate, a family member or a health careprofessional) to the patient while the patient is in a state of seizure.Thus, one of the advantages of the formulations according to the presentinvention is the ability to administer them in an acute therapeuticenvironment to treat the seizure victim, for example, nasally. Among thebeneficial therapeutic effects that may be imparted by acute dosing ofbenzodiazepine anticonvulsants, such as nasal dosing, are: reduction inthe severity of the seizure (e.g. general relaxation of the muscles,reduction in seizure-induced anxiety experienced by the patient and ageneral impartation of a feeling of well-being to the patient),reduction in the duration of the seizure, reduction in the probabilitythat the patient will experience a repeat seizure, an increase in theinterval between the current seizure and the next seizure. Thus, themexazolam formulations of the invention, and in particular nasalformulations, provide fast onset of therapeutic benefit—in someinstances less than about 30 minutes, less than about 15 minutes, lessthan about 10 minutes, and in some cases less than about 5 minutes. Themexazolam formulations of the invention, and in particular nasalformulations, also provide convenient administration of atherapeutically beneficial drug to a patient that does not requireintravenous drug administration or rectal drug administration.

Often seizures, particularly severe tonic or tonic-clonic seizures, willbe presaged by one or more aura events that will be familiar to thepatient or those familiar with the patient. These auras are practicallysui generis for each patient, but may be classified as audible, visual,olfactory or tactile sensations that usually, or typically, precedes apatient's experiencing a seizure. In some embodiments of the invention,the method includes prompt administration of a preparation of abenzodiazepine drug according to the invention during the aura. In someembodiments, such intra-aural administration of benzodiazepine drug, forexample by nasal administration, will prevent or at least ameliorate theeffects (intensity, duration or both) of the impending seizure. Thus, inthe context of this invention, prevention of seizure refers to atemporary forestalling of the onset of seizure, either with or withoutthe benefit of a warning aura.

Midazolam(8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo(1,5-a)benzodiazepine)

Midazolam is a tricyclic benzodiazepine having anxiolytic, amnesic,hypnotic, anticonvulsant, skeletal muscle relaxant and sedativeproperties. Midazolam is considered soluble in water at a pH lower thanabout 4, but is relatively insoluble in most aqueous solutions atneutral pH (e.g. about 6 to 8). Thus it is desirable in some embodimentsfor aqueous nasal preparations of midazolam to have a pH above about5.5, preferably above about 6.0, or above about 6.5. In some preferredembodiments, the pH is between about 6 and 9, between about 6 and 8. Itis considered that preparations of midazolam are particularly suitablefor nasal administration as the lipid-soluble (at approximately neutralpH) midazolam is rapidly absorbed across nasal mucosa, leading toefficient uptake of midazolam. It is further considered that midazolammay be formulated in a non-aqueous delivery vehicle, such as is known inthe aerosol administration art, such as hydrofluorocarbon propellants,hydrocarbon propellants, etc.

The dosage of midazolam varies by indication, however it is expectedthat a therapeutic dose will be in the range of about 0.1 to about 20,preferably about 0.2 to about 10 mg per dose, from 1 to 8, preferablyfrom 2 to 8, and in some preferred embodiments about 4 to about 6 timesper day. Midazolam may be manufactured using the process disclosed inone of U.S. Pat. No. 4,280,957 or 5,831,089, each of which isincorporated herein by reference in its entirety.

In some embodiments, midazolam is used alone or in combination withother drugs to provide an anxiolytic effect, an anticonvulsant effect, asedative effect, a skeletal muscle relaxant effect, an amnesic effect orcombinations of the foregoing effects.

In some embodiments, midazolam is used alone or in combination withanother anticonvulsant drug to treat seizure, protect against seizure,reduce or ameliorate the intensity of seizure, reduce or ameliorate thefrequency of seizure, and/or prevent occurrence or re-occurrence ofseizure. Midazolam may be administered by the patient or other person(such as a healthcare professional) while the patient is in anon-seizing state to protect against seizure. Even where protectionagainst seizure is not absolute, administration of midazolam may reduceor ameliorate the intensity of seizure and/or reduce or ameliorate thefrequency of seizure. In some embodiments, administration of midazolammay prevent occurrence of seizure. In some embodiments, especially wherethe patient is prone to experiencing serial seizures or statusepilepticus, administration of midazolam may aid in interrupting theseizure cycle and may thus prevent the re-occurrence of seizure. Inaddition to the benzodiazepines (such as diazepam), otheranti-convulsant drugs may be combined with midazolam to provide asynergistic anticonvulsant effect.

Midazolam may also be administered by another person (e.g. anacquaintance or associate, a family member or a health careprofessional) to the patient while the patient is in a state of seizure.Thus, one of the advantages of the formulations according to the presentinvention is the ability to administer them in an acute therapeuticenvironment to treat the seizure victim, for example, nasally. Among thebeneficial therapeutic effects that may be imparted by acute dosing ofbenzodiazepine anticonvulsants, such as nasal dosing, are: reduction inthe severity of the seizure (e.g. general relaxation of the muscles,reduction in seizure-induced anxiety experienced by the patient and ageneral impartation of a feeling of well-being to the patient),reduction in the duration of the seizure, reduction in the probabilitythat the patient will experience a repeat seizure, an increase in theinterval between the current seizure and the next seizure. Thus, themidazolam formulations of the invention, and in particular nasalformulations, provide fast onset of therapeutic benefit—in someinstances less than about 30 minutes, less than about 15 minutes, lessthan about 10 minutes, and in some cases less than about 5 minutes. Themidazolam formulations of the invention, and in particular nasalformulations, also provide convenient administration of atherapeutically beneficial drug to a patient that does not requireintravenous drug administration or rectal drug administration.

Often seizures, particularly severe tonic or tonic-clonic seizures, willbe presaged by one or more aura events that will be familiar to thepatient or those familiar with the patient. These auras are practicallysui generis for each patient, but may be classified as audible, visual,olfactory or tactile sensations that usually, or typically, precedes apatient's experiencing a seizure. In some embodiments of the invention,the method includes prompt administration of a preparation of abenzodiazepine drug according to the invention during the aura. In someembodiments, such intra-aural administration of benzodiazepine drug, forexample by nasal administration, will prevent or at least ameliorate theeffects (intensity, duration or both) of the impending seizure. Thus, inthe context of this invention, prevention of seizure refers to atemporary forestalling of the onset of seizure, either with or withoutthe benefit of a warning aura.

Temazepam(7-chloro-1-methyl-5-phenyl-3-hydroxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one)

Temazepam is a benzodiazepine drug having sedative, tranquilizing,anticonvulsant, amnesic and muscle relaxing properties. It is classifiedas an anxiolytic. Temazepam has also been shown to be useful in thetreatment of nausea. The dosage of temazepam varies by indication,however it is expected that a therapeutic dose will be in the range ofabout 1 to about 50, preferably about 5 to about 30 mg per dose, from 1to 8, preferably from 2 to 8, and in some preferred embodiments about 4to about 6 times per day. Temazepam may be manufactured using theprocess disclosed in U.S. Pat. No. 3,340,253 or 3,374,225, each of whichis incorporated herein by reference in its entirety.

In some embodiments, temazepam is used alone or in combination withother drugs to provide an anxiolytic effect, an anticonvulsant effect, asedative effect, a skeletal muscle relaxant effect, an amnesic effect orcombinations of the foregoing effects.

In some embodiments, temazepam is used alone or in combination withanother anticonvulsant drug to treat seizure, protect against seizure,reduce or ameliorate the intensity of seizure, reduce or ameliorate thefrequency of seizure, and/or prevent occurrence or re-occurrence ofseizure. Temazepam may be administered by the patient or other person(such as a healthcare professional) while the patient is in anon-seizing state to protect against seizure. Even where protectionagainst seizure is not absolute, administration of temazepam may reduceor ameliorate the intensity of seizure and/or reduce or ameliorate thefrequency of seizure. In some embodiments, administration of temazepammay prevent occurrence of seizure. In some embodiments, especially wherethe patient is prone to experiencing serial seizures or statusepilepticus, administration of temazepam may aid in interrupting theseizure cycle and may thus prevent the re-occurrence of seizure. Inaddition to the benzodiazepines (such as diazepam), otheranti-convulsant drugs may be combined with temazepam to provide asynergistic anticonvulsant effect.

Temazepam may also be administered by another person (e.g. anacquaintance or associate, a family member or a health careprofessional) to the patient while the patient is in a state of seizure.Thus, one of the advantages of the formulations according to the presentinvention is the ability to administer them in an acute therapeuticenvironment to treat the seizure victim, for example, nasally. Among thebeneficial therapeutic effects that may be imparted by acute dosing ofbenzodiazepine anticonvulsants, such as nasal dosing, are: reduction inthe severity of the seizure (e.g. general relaxation of the muscles,reduction in seizure-induced anxiety experienced by the patient and ageneral impartation of a feeling of well-being to the patient),reduction in the duration of the seizure, reduction in the probabilitythat the patient will experience a repeat seizure, an increase in theinterval between the current seizure and the next seizure. Thus, thetemazepam formulations of the invention, and in particular nasalformulations, provide fast onset of therapeutic benefit—in someinstances less than about 30 minutes, less than about 15 minutes, lessthan about 10 minutes, and in some cases less than about 5 minutes. Thetemazepam formulations of the invention, and in particular nasalformulations, also provide convenient administration of atherapeutically beneficial drug to a patient that does not requireintravenous drug administration or rectal drug administration.

Often seizures, particularly severe tonic or tonic-clonic seizures, willbe presaged by one or more aura events that will be familiar to thepatient or those familiar with the patient. These auras are practicallysui generis for each patient, but may be classified as audible, visual,olfactory or tactile sensations that usually, or typically, precedes apatient's experiencing a seizure. In some embodiments of the invention,the method includes prompt administration of a preparation of abenzodiazepine drug according to the invention during the aura. In someembodiments, such intra-aural administration of benzodiazepine drug, forexample by nasal administration, will prevent or at least ameliorate theeffects (intensity, duration or both) of the impending seizure. Thus, inthe context of this invention, prevention of seizure refers to atemporary forestalling of the onset of seizure, either with or withoutthe benefit of a warning aura.

Pharmaceutically Acceptable Salts

Benzodiazepines have the generally basic structure of formula I:

wherein R₁-R₅ are substituents. In particular embodiments, R₁ is anoptionally substituted alkyl or forms a ring with R₄, R₂ is a halogen(e.g. Cl, Br), R₃ is optionally substituted aryl (e.g. 2-Chloro or2-Fluorophenyl), R₅ is H or OH, R₄ and R₄′ together form a carbonyl(C═O) with the carbon to which they are attached or R₄ and R₁ form anoptionally substituted heterocyclic ring with the diazepam ring atoms towhich they are respectively attached; R₃′ and R₆ together form a doublebond or may be combined to form an optionally substituted heterocyclicring along with the diazepam ring atoms to which they are respectivelyattached. Such basic compounds may form acid addition salts withpharmaceutically acceptable acids, such as pharmaceutically acceptablemineral acids and pharmaceutically acceptable organic acids.

Pharmaceutically acceptable mineral acids include HCl, H₂SO₄, H₂SO₃,H₃PO₄, H₃PO₃, and others that will be recognized by those of skill inthe art. Pharmaceutically acceptable organic acids include acetic acid,benzoic acid, tartaric acid, citric acid, oxalic acid, maleic acid,malonic acid, etc. Thus, in some embodiments, the pharmaceuticallyacceptable acid may be selected from the group consisting of:1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acidascorbic acid (L),aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid(+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproicacid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid,cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acidfumaricacid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconicacid (D), glucuronic acid (D), glutamic acid, glutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid,hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid,lauric acid, maleic acid, malic acid (−L), malonic acid, mandelic acid(DL), methanesulfonic acid, benzenesulfonic acid (besylic acid),naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinicacid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid,phosphoric acid, proprionic acid, pyroglutamic acid (−L), salicylicacid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaricacid (+L), thiocyanic acid, toluenesulfonic acid (p) and undecylenicacid. Other pharmaceutically acceptable acids may be pharmaceuticallyacceptable acidic (anionic) polymers or pharmaceutically acceptableamphoteric polymers. One skilled in the art will recognize that otherbasic active pharmaceutical ingredients may be combined with theforegoing acids to produce acid addition salts. Likewise the personskilled in the art will recognize that in some embodiments it may beadvantageous that some or all of the added acid be an activepharmaceutical ingredient in its own right.

In some embodiments, the invention provides nasal compositionscomprising one or more acidic pharmaceutically active ingredients. It isconsidered well within the ordinary skill in the art to determine whichof the compounds set for the above are acidic. Such compounds may beprepared as base addition salts, e.g. by the addition of one or moremineral bases (e.g. NaOH, KOH, NaHCO₃, Na₂CO₃, NH₃) or organic bases. Itis considered within the skill in the art to choose a pharmaceuticallyacceptable base.

Known benzodiazepine compounds have anxiolytic, anticonvulsant, sedativeand/or skeletal muscle relaxant effect. The term “anticonvulsant”includes treatment of seizures, protection against seizure, reduction oramelioration of the intensity of seizure, reduction or amelioration ofthe frequency of seizure, and/or prevention of the occurrence orre-occurrence of seizure. In this regard, treatment of seizure includescessation of an ongoing seizure, reduction in the severity of an ongoingseizure, reduction in the duration of an ongoing seizure. Protectionagainst seizure includes forestalling an oncoming seizure.

Carrier System

Vitamin E is a class of fat soluble methylated phenols. There are atleast eight naturally-occurring compounds that comprise this class:α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol,β-tocotrienol, γ-tocotrienol, and δ-tocotrienol, all of which may beused in the compositions and methods of the present invention. There aremultiple isomers of each of these compounds, all of which may be used inthe compositions and methods of the present invention. There are alsomultiple esters of each of these compounds, including tocophersolan, allof which may be used in the compositions and methods of the presentinvention. As used herein, Vitamin E refers to any of the natural orsynthetic tocopherols, tocotrienols, any isomers thereof, any estersthereof, any analogs or derivatives thereof, or any combinationsthereof.

The compounds that comprise Vitamin E are antioxidants. There is alsoevidence that they can prevent, delay the onset of, or ameliorate thesymptoms of heart disease, cancer, cataracts, macular degeneration,glaucoma, Alzheimer's, and Parkinson's disease.

The inventors have found that Vitamin E can provide an effective carrierfor benzodiazepine drugs. In some embodiments, benzodiazepines aresoluble, or partially soluble, in Vitamin E. In some embodiments,Vitamin E may be present as microparticles, nanoparticles, or anycombination thereof. Furthermore, use of Vitamin E can have the addedbenefit of either avoiding irritation of sensitive mucosal membranesand/or soothing irritated mucosal membranes.

Vitamin E is generally classified as hydrophobic, and when used as acarrier may be limited to formulations as an emulsion. However,emulsions can have several drawbacks. For instance, they may bedifficult to create and can be highly unstable. Additionally, they canleave an oily film on the surface of the skin. Thus, to avoid thedrawbacks of emulsions, some embodiments of the present inventioncomprise solutions of one or more benzodiazepine drugs in Vitamin E andone or more lower alkyl alcohols or one or more lower alkyl glycols, orany combinations thereof.

Lower alkyl alcohols are those with six or fewer carbon atoms. Thus, anyof ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, anyisomers thereof, or any combinations thereof can be used.

Lower alkyl glycols are those with six or fewer carbon atoms. Thus, anyof ethylene glycol, propylene glycol, butylene glycol, pentylene glycol,any isomers thereof, or any combinations thereof can be used.

Additional Excipients

In some embodiments, a composition comprises at least one penetrationenhancer in addition to a benzodiazepine drug, a natural or synthetictocopherol or tocotrienol, and an alcohol or glycol. In someembodiments, the penetration enhancer is at least one alkyl glycoside.In some embodiments, the alkyl glycoside refers to any sugar joined toany hydrophobic alkyl, as described in U.S. Pat. No. 5,661,130, which isincorporated herein by reference in its entirety. The hydrophobic alkylcan be any suitable length, for example about 9 to about 24 carbons inlength, especially about 10 to about 14 carbons in length. Thehydrophobic alkyl can be branched and/or partially or whollyunsaturated. The alkyl may be joined to the saccharide core for examplethrough a carbonyl group, whereby an ester group may be formed. Asuitable alkyl glycoside will have the characteristics of beingnontoxic, nonionic, and capable of increasing the absorption of abenzodiazepine drug when it is administered intranasally as describedherein. Exemplary saccharides that may be covalently joined to an alkylaccording to the present invention include glucose, maltose,maltotriose, maltotetrose, sucrose and trehalose. Exemplary alkylglycosides that may be employed include octyl-, nonyl-, decyl-,undecyl-, dodecyl, tridecyl, tetradecyl, pentadecyl, octadecyl α- orβ-D-maltoside, -glucoside or sucroside. In some embodiments, thepreferred glycosides include maltose, sucrose or glucose linked byglycosidic linkage to an alkyl chain of 9, 10, 12, 14, 16, 18 or 20carbon atoms. Specific excipients that may be employed in a nasalcomposition according to the invention include alkylsaccharide isdodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrosemonostearate, sucrose distearate, and/or combinations of two or morethereof. Alkyl glycosides that are particularly considered useful inembodiments of the invention include those marketed under the nameIntravail® by Aegis Therapeutics, LLC, San Diego, Calif. Other alkylglycosides may be selected from those having a hydrophile-lipophilebalance (HLB) number of from about 10-20, especially about 11-15. TheHLB number may be determined as set forth in the publicationUS2009/0047347, published on 19 Feb. 2009, the entirety of which, andespecially paragraphs [0075]-[0079], is incorporated herein byreference. Where present, the amount of alkyl glycoside in thecomposition is sufficient to enhance the absorption of a benzodiazepinedrug administered by the intranasal route. In some embodiments, theamount of alkyl glycoside in the composition is selected so as toenhance absorption of the benzodiazepine drug, while at the same timenot significantly irritating the nasal mucosa. In some embodiments, theamount of alkyl glycoside in the composition is in a range of about0.01% (w/v) to about 1% (w/v). In some embodiments, the amount of alkylglycoside in the composition is in a range of about 0.05% (w/v) to about0.5% (w/v), or about 0.125% (w/v) to about 0.5% (w/v).

The term “penetration enhancer”, means any material which acts toincrease absorption across the mucosa and/or increases bioavailability.In some embodiments, such materials include mucolytic agents,degradative enzyme inhibitors and compounds which increase permeabilityof the mucosal cell membranes. Whether a given compound is an “enhancer”can be determined by comparing two formulations comprising anon-associated, small polar molecule as the drug, with or without theenhancer, in an in vivo or good model test and determining whether theuptake of the drug is enhanced to a clinically significant degree. Theenhancer should not produce any problems in terms of chronic toxicitybecause in vivo the enhancer should be non-irritant and/or rapidlymetabolized to a normal cell constituent that does not have anysignificant irritant effect.

In some embodiments, preferred enhancing materials lysophospholipids,for example lysophosphatidylcholine obtainable from egg or soy lecithin.Other lysophosphatidylcholines that have different acyl groups as wellas lyso compounds produced from phosphatidylethanolamines andphosphatidic acid which have similar membrane modifying properties maybe used. Acyl carnitines (e.g. palmitoyl-dl-carnitine-chloride) is analternative. In some embodiments, a suitable concentration is from 0.02to 20% (w/v).

In some embodiments, enhancing agents that are appropriate includechelating agents (EGTA, EDTA, alginates), surface active agents(especially non-ionic materials), acyl glycerols, fatty acids and salts,tyloxapol and biological detergents listed in the SIGMA Catalog, 1988,page 316-321 (which is incorporated herein by reference). Also agentsthat modify the membrane fluidity and permeability are appropriate suchas enamines (e.g. phenylalanine enamine of ethylacetoacetate), malonates(e.g. diethyleneoxymethylene malonate), salicylates, bile salts andanalogues and fusidates. Suitable concentrations are up to 20% (w/v).

Thus, in some embodiments, the invention provides a pharmaceuticalcomposition for nasal administration comprising: a benzodiazepine drug,one or more natural or synthetic tocopherols or tocotrienols, or anycombinations thereof, in an amount from about 30% to about 95% (w/w);one or more alkyl glycosides; and one or more alcohols or glycols, orany combinations thereof, in an amount from about 10% to about 70%(w/w), in a pharmaceutically-acceptable formulation for administrationto one or more nasal mucosal membranes of a patient. In someembodiments, the alkyl glycoside is an Intravail® brand alkyl glycoside.In some embodiments, the alkyl glycoside is dodecyl maltoside,tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrosedistearate, and/or a combination of two or more thereof. In someembodiments, the alkyl glycoside is dodecyl maltoside. In someembodiments, the alkyl glycoside is tetradecyl maltoside. In someembodiments, the alkyl glycoside is sucrose dodecanoate. In someembodiments, the alkyl glycoside is sucrose monostearate. In someembodiments, the alkyl glycoside is sucrose distearate. In someembodiments, the alkyl glycoside is a combination of two or more ofdodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrosemonostearate, or sucrose distearate.

Thus, in some embodiments, the invention provides a pharmaceuticalcomposition for nasal administration comprising: a benzodiazepine drug,which benzodiazepine drug comprises microparticles, nanoparticles orboth, one or more natural or synthetic tocopherols or tocotrienols, orany combinations thereof, in an amount from about 30% to about 95%(w/w); one or more alkyl glycosides; and one or more alcohols orglycols, or any combinations thereof, in an amount from about 10% toabout 70% (w/w), in a pharmaceutically-acceptable formulation foradministration to one or more nasal mucosal membranes of a patient. Insome embodiments, the alkyl glycoside is an Intravail® brand alkylglycoside. In some embodiments, the alkyl glycoside is dodecylmaltoside, tetradecyl maltoside, sucrose dodecanoate, sucrosemonostearate, sucrose distearate, and/or a combination of two or morethereof. In some embodiments, the alkyl glycoside is dodecyl maltoside.In some embodiments, the alkyl glycoside is tetradecyl maltoside. Insome embodiments, the alkyl glycoside is sucrose dodecanoate. In someembodiments, the alkyl glycoside is sucrose monostearate. In someembodiments, the alkyl glycoside is sucrose distearate. In someembodiments, the alkyl glycoside is a combination of two or more ofdodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrosemonostearate, or sucrose distearate.

Mucosal Membrane Preparations

Mucosal membrane preparations are generally administered in meteredsprays having volumes of less than 250 μL, preferably less than 150 μL,and ideally from 25 to 100 μL. Although not prohibited in thisinvention, administration of volumes larger than about 300 μL, per doseusually exceeds the absorption capacity of the membranes. This resultsin a large portion of the pharmaceutically-active ingredient being lost.

The dosage volume of preparations, in particular nasal preparations,preferably ranges from 25 to 100 μL. Volumes in excess of theaforementioned ranges may bypass the sinuses and flow down the back ofthe throat where the excess is swallowed.

Alprazolam

The dosage of alprazolam varies by indication, however it is expectedthat a therapeutic dose will be in the range of about 0.5 to about 4,preferably about 1 to about 2 mg per dose, from 1 to 8, preferably from2 to 8, and in some preferred embodiments about 4 to about 6 times perday. Alprazolam may be manufactured using the process disclosed in U.S.Pat. No. 3,987,052, which is incorporated herein by reference in itsentirety.

As a nasal formulation, alprazolam may be administered in 25 to 250 μLmetered sprays. In some preferred embodiments, alprazolam isadministered in 50 to 150 μL, especially about 100 μL, metered sprays

Diazepam

The dosage of diazepam may vary by indication, however it is expectedthat a therapeutic dose will be in the range of about 1 to about 20,preferably about 2 to about 10 mg per dose, from 1 to 8, preferably from2 to 8, and in some preferred embodiments about 4 to about 6 times perday. Diazepam may be manufactured using the process disclosed in one ofU.S. Pat. Nos. 3,371,085, 3,109,843, 3,136,815 or 3,102,116, each ofwhich is incorporated herein by reference in its entirety.

As a nasal formulation, diazepam may be administered in 25 to 250 μLmetered sprays. In some preferred embodiments, diazepam is administeredin 50 to 150 μL, especially about 100 μL, metered sprays.

Flurazepam

The dosage of flurazepam varies by indication, however it is expectedthat a therapeutic dose will be in the range of about 5 to 40,preferably about 20 to about 35 mg per dose, from 1 to 8, preferablyfrom 2 to 8, and in some preferred embodiments about 4 to about 6 timesper day. Flurazepam may be manufactured using the process disclosed inU.S. Pat. No. 3,567,710 or 3,299,053, each of which is incorporatedherein by reference in its entirety.

As a nasal formulation, flurazepam may be administered in 25 to 250 μLmetered sprays. In some preferred embodiments, flurazepam isadministered in 50 to 150 μL, especially about 100 μL, metered sprays.

Lorazepam

The dosage of Lorazepam varies by indication, however it is expectedthat a therapeutic dose will be in the range of about 0.1 to about 10,preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferablyfrom 2 to 8, and in some preferred embodiments about 4 to about 6 timesper day. Lorazepam may be manufactured using the process disclosed inU.S. Pat. No. 3,296,249, which is incorporated herein by reference inits entirety.

As a nasal formulation, lorazepam may be administered in 25 to 250 μLmetered sprays. In some preferred embodiments, lorazepam is administeredin 50 to 150 μL, especially about 100 μL, metered sprays.

Medazepam

The dosage of medazepam varies by indication, however it is expectedthat a therapeutic dose will be in the range of about 0.1 to about 10,preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferablyfrom 2 to 8, and in some preferred embodiments about 4 to about 6 timesper day. Medazepam may be manufactured using the process disclosed inU.S. Pat. No. 3,243,427, which is incorporated herein by reference inits entirety.

As a nasal formulation, medazepam may be administered in 25 to 250 μLmetered sprays. In some preferred embodiments, medazepam is administeredin 50 to 150 μL, especially about 100 μL, metered sprays.

Mexazolam

The dosage of mexazolam varies by indication, however it is expectedthat a therapeutic dose will be in the range of about 0.1 to about 10,preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferablyfrom 2 to 8, and in some preferred embodiments about 4 to about 6 timesper day. Mexazolam may be manufactured using the process disclosed inU.S. Pat. No. 3,722,371, which is incorporated herein by reference inits entirety.

As a nasal formulation, mexazolam may be administered in 25 to 250 μLmetered sprays. In some preferred embodiments, mexazolam is administeredin 50 to 150 μL, especially about 100 μL, metered sprays.

Midazolam

The dosage of midazolam varies by indication, however it is expectedthat a therapeutic dose will be in the range of about 0.1 to about 20,preferably about 0.2 to about 10 mg per dose, from 1 to 8, preferablyfrom 2 to 8, and in some preferred embodiments about 4 to about 6 timesper day. Midazolam may be manufactured using the process disclosed inone of U.S. Pat. No. 4,280,957 or 5,831,089, each of which isincorporated herein by reference in its entirety.

As a nasal formulation, midazolam may be administered in 25 to 250 μLmetered sprays. In some preferred embodiments, midazolam is administeredin 50 to 150 μL, especially about 100 μL, metered sprays.

Temazepam

The dosage of temazepam varies by indication, however it is expectedthat a therapeutic dose will be in the range of about 1 to about 50,preferably about 5 to about 30 mg per dose, from 1 to 8, preferably from2 to 8, and in some preferred embodiments about 4 to about 6 times perday. Temazepam may be manufactured using the process disclosed in U.S.Pat. No. 3,340,253 or 3,374,225, each of which is incorporated herein byreference in its entirety.

As a nasal formulation, temazepam may be administered in 25 to 250 μLmetered sprays. In some preferred embodiments, temazepam is administeredin 50 to 150 μL, especially about 100 μL, metered sprays.

Formulation

Some embodiments comprise administering to one or more mucosal membranesof a patient a therapeutically effective amount of one or morebenzodiazepine drugs, or pharmaceutically-acceptable salts thereof. Someembodiments of the composition disclose a composition comprising one ormore benzodiazepine drugs or pharmaceutically-acceptable salts thereofin a concentration up to about 600 mg/mL. Other compositions disclose acomposition comprising one or more benzodiazepine drugs orpharmaceutically-acceptable salts thereof in a concentration of about 10mg/mL up to about 250 mg/mL. Further, some embodiments disclose acomposition comprising one or more benzodiazepine drugs orpharmaceutically-acceptable salts thereof in a concentration of about 20mg/mL up to about 50 mg/mL.

Some embodiments disclose a carrier system that is about 50% to about90% (w/w) Vitamin E and about 10% to about 50% (w/w) lower alcohol orlower alkyl glycol, or any combinations thereof. Some embodimentsdisclose a carrier system that is about 65% to about 75% (w/w) Vitamin Eand about 25% to about 35% (w/w) lower alkyl alcohol or lower alkylglycol, or any combinations thereof. Further, some embodiments disclosea carrier system that is about 70% (w/w) Vitamin E and about 30% (w/w)lower alkyl alcohol or lower alkyl glycol, or any combinations thereof.

Some embodiments of the invention provide a method of administering thebenzodiazepine drug composition to a patient. The preferred embodimentcomprises use of diazepam. Some embodiments of the method disclose adosage level of diazepam of about 1.0 mg to about 20.0 mg untilachievement of the desired result. Other dosage levels disclose a dosagelevel of about 2.0 mg to about 15.0 mg until the desired result isachieved. Some embodiments disclose a dosage level of about 5.0 mg toabout 10.0 mg until the desired result is achieved.

In some embodiments of the method, the dosage volume ranges from about10 μL to about 200 μL. In some embodiments, the dosage volume rangesfrom about 20 μL to about 180 μL. Further, some embodiments disclose adosage volume of about 50 μL to about 140 μL. In some embodiments, thedosage volume is 50 μL, 75 μL or 100 μL per nostril.

Formulation Process

In some embodiments, the composition for nasal administration issubstantially free of benzodiazepine microparticles, nanoparticles orcombinations thereof. In some embodiments, the composition is made byslowly warming or heating the Vitamin E until it is liquefied. Next, theone or more benzodiazepine drugs are added. The mixture is stirred andheated until the one or more benzodiazepine drugs dissolve or aresubstantially dissolved. Next, the one or more alcohols or glycols, orany combinations thereof, are added to the composition. This compositionis stirred until a less viscous composition is achieved.

The formulation process may be adjusted to take into considerationvariations in the formulation. For example, as depicted in FIG. 4,formulations comprising both benzyl alcohol and ethanol may beformulated by first combining Vitamin E, benzyl alcohol and ethanol(e.g., dehydrated alcohol, USP), mixing until the ingredients arehomogenous, heating the mixture to about 45° C. (±2° C.), adding alkylglocoside and mixing until the alkyl glycoside is dissolved and thesolution is homogenous, adding benzodiazepine (e.g., diazepam) whilemaintaining the mixture at about 45° C., cooling the solution to about25° C. (±2° C.) and adding ethanol (Q.S.) to achieve the final targetweight of solution, mixing well to assure homogeneity. Solutionsmanufactured according to this process may be formulated in differentconcentrations of diazepam. For example, some embodiments of theinvention include diazepam formulations summarized in the followingtable. While diazepam is used as an illustration in FIG. 4 and thefollowing table, any benzodiazepines may also be used, such asalprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam,clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam,midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam,prazepam, quazepam, triazolam, temazepam, loprazolam, anypharmaceutically-acceptable salts thereof, and any combinations thereof.

NRL-1 Quantitative Composition. In some embodiments, the formulationsare for nasal administration.

Solution Concentration Component 50 mg/mL 75 mg/mL 100 mg/mL Vitamin E56.47 mg 56.47 mg 56.47 mg Benzyl alcohol 10.50 mg 10.50 mg 10.50 mgDiazepam 5.00 mg 7.50 mg 10.00 mg Intravail A3 ® 0.25 mg 0.25 mg 0.25 mgDehydrated ethanol q.s. to 100 μL q.s. to 100 μL q.s. to 100 μL

In some embodiments, the aforementioned formulations are sterilesolutions with a bacteria count of 10 below the allowable level on a permL basis. Additionally, pathogens are preferably absent. In someembodiments, the solutions are self-preserving, self-sterile or both.

In some embodiments, the benzodiazepine drug is formulated as amicroparticulate and/or nanoparticulate suspension of thebenzodiazepine. Preparation of microparticulate and nanoparticulatebenzodiazepine may be accomplished by methods such as milling, etc. Suchmethods are known to those skilled in the art.

FIG. 5 depicts one embodiment of a process of manufacturing a suspensionof benzodiazepine according to the instant invention. First, thebenzodiazepine (e.g., diazepam) is sieved to produce a micronizedbenzodiazepine (e.g., diazepam). The micronized benzodiazepine (e.g.,diazepam) is then split into two intermediates products—Diazepam A (highpressure) is a small particle size (mean particle size <2000 nm) andDiazepam B (low pressure) is a large particle size (mean particlediameter >2000 nm). After in-process testing, the two intermediateproducts are combined with one or more excipients in correct proportionsto produce a bimodal particle suspension having a pre-selected meanparticle diameter, which in some embodiments is greater than 2000 nm. Insome embodiments, the excipients are prepared according to the secondcolumn in FIG. 5, e.g. by first combining propylene glycol, water andvitamin E polyethylene glycol succinate to form a mixture and heatingthe mixture until the ingredients are dissolved, then addingmethylparaben, propyl paraben and Intravail™ (alkyl glycoside) to themixture and mixing until the newly added ingredients are dissolved, andfinally cooling the mixture, e.g. to 25° C.±2° C. The excipients canthen be combined with Micronized Diazepam A and Micronized Diazepam Band mixed vigorously to disperse the micronized Diazepam to form thesuspension. Next, povidone is added to the mixture, which is mixed untilthe povidone is fully dissolved. Finally, the suspension is brought toits final target weight with purified water and mixed well to achievehomogeneity. The final product can then be filled into suitablecontainers. In some embodiments, 3 mL may be filled into 4 mL amberglass vials with PTFE lined phenolic closures, though other containersare of course possible and contemplated within the scope of theinvention. As diazepam is depicted in FIG. 5 as an exemplarybenzodiazepine, any benzodiazepines, such as alprazolam, brotizolam,chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam,diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam,medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam,triazolam, temazepam, loprazolam, any pharmaceutically-acceptable saltsthereof, and any combinations thereof may also be employed.

In some embodiments, the aforementioned formulations are sterilesuspensions with a bacteria count of 10 below the allowable level on aper mL basis. Additionally, pathogens are preferably absent. In someembodiments, the suspensions are self-preserving, self-sterile or both.

In some embodiments, the benzodiazepine drug is formulated as asolution. It is considered an aspect of the invention that employment ofmicroparticulate and/or nanoparticulate benzodiazepine drug during theprocess of preparing the formulation, can improve the overall solubilityof the benzodiazepine drug in the solvent system.

Additional Active and Inactive Ingredients

Additionally, some embodiments of the compositions and methods of usingthe compositions comprise an additional ingredient in the compositionselected from active ingredients. By way of non-limiting example, suchactive ingredients include insulin, calcitonins (for example porcine,human, salmon, chicken, or eel) and synthetic modifications thereof,enkephalins, LHRH and analogues (Nafarelin, Buserelin, Zolidex), GHRH(growth hormone releasing hormone), nifedipin, THF (thymic humoralfactor), CGRP (calcitonin gene related peptide), atrial natriureticpeptide, antibiotics, metoclopramide, ergotamine, Pizotizin, nasalvaccines (particularly HIV vaccines, measles, rhinovirus Type 13 andrespiratory syncitial virus), pentamidine, CCK (Cholecystikinine),DDVAP, Interferons, growth hormone (solatotropir polypeptides or theirderivatives (preferably with a molecular weight from 1000 to 300000),secretin, bradykinin antagonists, GRF (Growth releasing factor), THF,TRH (Thyrotropin releasing hormone), ACTH analogues, IGF (Insulin likegrowth factors), CGRP (Calcitorin gene related peptide) AtrialNatriuretic peptide, Vasopressin and analogues (DDAVP, Lypressin),Metoclopramide, Migraine treatment (Dihydroergotamine, Ergometrine,Ergotamine, Pizotizin), Nasal Vaccines (Particularly AIDS vaccines)FACTOR VIII, Colony Stimulating factors, G-CSF (granulocyte-colonystimulating factor), EPO (Erythropoitin) PTH (Parathyroid hormone) orpharmaceutically acceptable salts or combinations thereof.

Additionally, some embodiments of the compositions and methods of usingthe compositions comprise an additional ingredient in the compositionselected from other anticonvulsants. By way of non-limiting example,such active ingredients include: paraldehyde; aromatic allylic alcohols(such as stiripentol); barbiturates (e.g. phenobarbitol, primidone,methylphenobarbital, metharbital and barbexaclone); bromides (such aspotassium bromide); carbamates (such as felbamate); carboxamides (suchas carbamazepine and oxcarbazepine); fatty acids (such as valproic acid,sodium valproate, and divalproex sodium, vigabatrin, progabide,tiagabine); fructose, topiramate, Gaba analogs (e.g. gabapentin andpregabalin); hydantoins (e.g. ethotoin, phenytoin, mephenytoin andfosphenytoin); oxazolidinediones (such as paramethadione, trimethadione,ethadione); propionates (e.g. beclamide), pyrimidinediones (e.g.primidone); pyrrolidines (e.g. brivaracetam, levetiracetam andseletracetam); succinimides (e.g. ethosuximide, phensuximide andmesuximide); sulfonamides (e.g. acetazolamide, sulthiame, methazolamideand zonisamide); triazines (such as lamotrigine); ureas (such aspheneturide, phenacemide); valproylamides (such as valpromide andvalnoctamide); as well as other anticonvulsants or pharmaceuticallyacceptable salts or combinations thereof.

Additionally, some embodiments of the compositions and methods of usingthe compositions comprise an additional ingredient in the compositionselected from other anticonvulsants. By way of non-limiting example,such active ingredients include: antibiotics and antimicrobial agentssuch as tetracyline hydrochloride, leucomycin, penicillin, penicillinderivatives, erythromycin, gentamicin, sulphathiazole and nitrofurazone;local anaesthetics such as benzocaine; vasoconstrictors such asphenylephrine hydrochloride, tetrahydrozoline hydrochloride, naphazolinenitrate, oxymetazoline hydrochloride and tramazoline hydrochloride;cardiotonics such as digitalis and digoxin; vasodilators such asnitroglycerine and papaverine hydrochloride; antiseptics such aschlorhexidine hydrochloride, hexylresorcinol, dequaliniumchloride andethacridine; enzymes such as lysozyme chloride, dextranase; bonemetabolism controlling agents such as vitamin D, active vitamin D andvitamin C; sex hormones; hypotensives; sedatives; anti-tumor agents;steroidal anti-inflammatory agents such as hydrocortisone, prednisone,fluticasone, prednisolone, triamcinolone, triamcinolone acetonide,dexamethasone, betamethasone, beclomethasone, and beclomethasonedipropionate; non-steroidal anti-inflammatory agents such asacetaminophen, aspirin, aminopyrine, phenylbutazone, medanamic acid,ibuprofen, diclofenac sodium, indomethacine, colchicine, and probenocid;enzymatic anti-inflammatory agents such as chymotrypsin and bromelainseratiopeptidase; anti-histaminic agents such as diphenhydraminehydrochloride, chloropheniramine maleate and clemastine; anti-allergicagents and antitussive-expectorant antasthmatic agents such as sodiumchromoglycate, codeine phosphate, and isoproterenol hydrochloride orpharmaceutically acceptable salts or combinations thereof.

Additionally, some embodiments of the compositions and methods of usingthe compositions comprise an additional inactive ingredient in thecomposition. By way of non-limiting example, minor amounts ofingredients such as stabilizers, coloring agents, pH adjusters,buffering agents, preservatives such as agents which may preventdegradation, wetting agents, and flavoring agents may also be present.Examples of coloring agents include β-carotene, Red No. 2 and BlueNo. 1. Examples of preservatives include stearic acid, ascorbyl stearateand ascorbic acid. Examples of corrigents include menthol and citrusperfume.

In some embodiments, the drug delivery system of the invention mayadvantageously comprise an absorption enhancer. The term “enhancer”,means any material which acts to increase absorption across the mucosaand/or increases bioavailability. In some embodiments, such materialsinclude mucolytic agents, degradative enzyme inhibitors and compoundswhich increase permeability of the mucosal cell membranes. Whether agiven compound is an “enhancer” can be determined by comparing twoformulations comprising a non-associated, small polar molecule as thedrug, with or without the enhancer, in an in vivo or good model test anddetermining whether the uptake of the drug is enhanced to a clinicallysignificant degree. The enhancer should not produce any problems interms of chronic toxicity because in vivo the enhancer should benon-irritant and/or rapidly metabolized to a normal cell constituentthat does not have any significant irritant effect.

In some embodiments, preferred enhancing materials lysophospholipids,for example lysophosphatidylcholine obtainable from egg or soy lecithin.Other lysophosphatidylcholines that have different acyl groups as wellas lyso compounds produced from phosphatidylethanolamines andphosphatidic acid which have similar membrane modifying properties maybe used. Acyl carnitines (e.g. palmitoyl-dl-carnitine-chloride) is analternative. In some embodiments, a suitable concentration is from 0.02to 20% (w/v).

In some embodiments, enhancing agents that are appropriate includechelating agents (EGTA, EDTA, alginates), surface active agents(especially non-ionic materials), acyl glycerols, fatty acids and salts,tyloxapol and biological detergents listed in the SIGMA Catalog, 1988,page 316-321 (which is incorporated herein by reference). Also agentsthat modify the membrane fluidity and permeability are appropriate suchas enamines (e.g. phenylalanine enamine of ethylacetoacetate), malonates(e.g. diethyleneoxymethylene malonate), salicylates, bile salts andanalogues and fusidates. Suitable concentrations are up to 20% (w/v).

In some embodiments, the invention takes advantage of delivery of a drugincorporated into or onto a bioadhesive microsphere with an addedpharmaceutical adjuvant applies to systems that contain active drug andmucolytic agent, peptidase inhibitors or non-drug polypeptide substratesingly or in combination. Suitably mucolytic agents are thiol-containingcompounds such as N-acetylcysteine and derivatives thereof. Peptideinhibitors include actinonin, amastatin, bestatin,chloroacetyl-HOLeu-Ala-Gly-NH.sub.2, diprotin A and B, ebelactone A andB, E-64, leupeptin, pepstatin A, phisphoramidon, H-Thr-(tBu)-Phe-Pro-OH,aprotinin, kallikrein, chymostatin, benzamidine, chymotrypsin andtrypsin. Suitable concentrations are from 0.01 to 10% (w/v). The personskilled in the art will readily be able to determine whether an enhancershould be included.

Administration

In some embodiments, the administration of the composition comprisesadministering at least a portion of the therapeutically effective amountof the composition onto at least one mucosal membrane. In someembodiments, the administration of the composition comprises spraying atleast a portion of the therapeutically effective amount of thecomposition into at least one nostril. In some embodiments, theadministration of the composition comprises spraying at least a portionof the therapeutically effective amount of the composition into eachnostril. In some embodiments, the administration of the compositioncomprises spraying a first quantity of the composition into the firstnostril, spraying a second quantity of the composition into a secondnostril, and optionally after a pre-selected time delay, spraying athird quantity of the composition into the first nostril. Someembodiments further comprise, optionally after a pre-selected timedelay, administering at least a fourth quantity of the composition tothe second nostril.

Alprazolam

The dosage of alprazolam varies by indication, however it is expectedthat a therapeutic dose will be in the range of about 0.5 to about 4,preferably about 1 to about 2 mg per dose, from 1 to 8, preferably from2 to 8, and in some preferred embodiments about 4 to about 6 times perday. Alprazolam may be manufactured using the process disclosed in U.S.Pat. No. 3,987,052, which is incorporated herein by reference in itsentirety.

As a nasal formulation, alprazolam may be administered in 25 to 250 μL,metered sprays. In some preferred embodiments, alprazolam isadministered in 50 to 150 μL, especially about 100 μL, metered sprays.In some embodiments, a first metered spray is applied to a first nostriland if necessary a second metered spray is applied to a second nostril.In some optional embodiments, a third metered spray is applied to thefirst nostril. In some embodiments, a fourth metered spray is applied tothe second nostril. In some embodiments, additional metered sprays areapplied to alternating nostrils until the full target therapeutic dosehas been administered to the patient. In some embodiments, there is atime increment of from several seconds to 5 minutes, preferably about 10seconds to about 1 minute, between applications of benzodiazepine drugto the same nostril. This allows time for the drug to cross the nasalmucosa and enter the blood stream. Multiple applications of meteredsprays to each nostril, optionally separated by a time interval, allowsadministration of a full therapeutic dose in increments small enough topermit full absorption of the benzodiazepine drug into the blood streamand avoid loss of drug down the back of the throat.

Diazepam

The dosage of diazepam may vary by indication, however it is expectedthat a therapeutic dose will be in the range of about 1 to about 20,preferably about 2 to about 10 mg per dose, from 1 to 8, preferably from2 to 8, and in some preferred embodiments about 4 to about 6 times perday. Diazepam may be manufactured using the process disclosed in one ofU.S. Pat. No. 3,371,085, 3,109,843, 3,136,815 or 3,102,116, each ofwhich is incorporated herein by reference in its entirety.

As a nasal formulation, diazepam may be administered in 25 to 250 μLmetered sprays. In some preferred embodiments, diazepam is administeredin 50 to 150 μL, especially about 100 μL, metered sprays. In someembodiments, a first metered spray is applied to a first nostril and ifnecessary a second metered spray is applied to a second nostril. In someoptional embodiments, a third metered spray is applied to the firstnostril. In some embodiments, a fourth metered spray is applied to thesecond nostril. In some embodiments, additional metered sprays areapplied to alternating nostrils until the full target therapeutic dosehas been administered to the patient. In some embodiments, there is atime increment of from several seconds to 5 minutes, preferably about 10seconds to about 1 minute, between applications of benzodiazepine drugto the same nostril. This allows time for the drug to cross the nasalmucosa and enter the blood stream. Multiple applications of meteredsprays to each nostril, optionally separated by a time interval, allowsadministration of a full therapeutic dose in increments small enough topermit full absorption of the benzodiazepine drug into the blood streamand avoid loss of drug down the back of the throat.

Flurazepam

The dosage of flurazepam varies by indication, however it is expectedthat a therapeutic dose will be in the range of about 5 to 40,preferably about 20 to about 35 mg per dose, from 1 to 8, preferablyfrom 2 to 8, and in some preferred embodiments about 4 to about 6 timesper day. Flurazepam may be manufactured using the process disclosed inU.S. Pat. No. 3,567,710 or 3,299,053, each of which is incorporatedherein by reference in its entirety.

As a nasal formulation, flurazepam may be administered in 25 to 250 μLmetered sprays. In some preferred embodiments, flurazepam isadministered in 50 to 150 μL, especially about 100 μL, metered sprays.In some embodiments, a first metered spray is applied to a first nostriland if necessary a second metered spray is applied to a second nostril.In some optional embodiments, a third metered spray is applied to thefirst nostril. In some embodiments, a fourth metered spray is applied tothe second nostril. In some embodiments, additional metered sprays areapplied to alternating nostrils until the full target therapeutic dosehas been administered to the patient. In some embodiments, there is atime increment of from several seconds to 5 minutes, preferably about 10seconds to about 1 minute, between applications of benzodiazepine drugto the same nostril. This allows time for the drug to cross the nasalmucosa and enter the blood stream. Multiple applications of meteredsprays to each nostril, optionally separated by a time interval, allowsadministration of a full therapeutic dose in increments small enough topermit full absorption of the benzodiazepine drug into the blood streamand avoid loss of drug down the back of the throat.

Lorazepam

The dosage of Lorazepam varies by indication, however it is expectedthat a therapeutic dose will be in the range of about 0.1 to about 10,preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferablyfrom 2 to 8, and in some preferred embodiments about 4 to about 6 timesper day. Lorazepam may be manufactured using the process disclosed inU.S. Pat. No. 3,296,249, which is incorporated herein by reference inits entirety.

As a nasal formulation, lorazepam may be administered in 25 to 250 μLmetered sprays. In some preferred embodiments, lorazepam is administeredin 50 to 150 μL, especially about 100 μL, metered sprays. In someembodiments, a first metered spray is applied to a first nostril and ifnecessary a second metered spray is applied to a second nostril. In someoptional embodiments, a third metered spray is applied to the firstnostril. In some embodiments, a fourth metered spray is applied to thesecond nostril. In some embodiments, additional metered sprays areapplied to alternating nostrils until the full target therapeutic dosehas been administered to the patient. In some embodiments, there is atime increment of from several seconds to 5 minutes, preferably about 10seconds to about 1 minute, between applications of benzodiazepine drugto the same nostril. This allows time for the drug to cross the nasalmucosa and enter the blood stream. Multiple applications of meteredsprays to each nostril, optionally separated by a time interval, allowsadministration of a full therapeutic dose in increments small enough topermit full absorption of the benzodiazepine drug into the blood streamand avoid loss of drug down the back of the throat.

Medazepam

The dosage of medazepam varies by indication, however it is expectedthat a therapeutic dose will be in the range of about 0.1 to about 10,preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferablyfrom 2 to 8, and in some preferred embodiments about 4 to about 6 timesper day. Medazepam may be manufactured using the process disclosed inU.S. Pat. No. 3,243,427, which is incorporated herein by reference inits entirety.

As a nasal formulation, medazepam may be administered in 25 to 250 μLmetered sprays. In some preferred embodiments, medazepam is administeredin 50 to 150 μL, especially about 100 μL, metered sprays. In someembodiments, a first metered spray is applied to a first nostril and ifnecessary a second metered spray is applied to a second nostril. In someoptional embodiments, a third metered spray is applied to the firstnostril. In some embodiments, a fourth metered spray is applied to thesecond nostril. In some embodiments, additional metered sprays areapplied to alternating nostrils until the full target therapeutic dosehas been administered to the patient. In some embodiments, there is atime increment of from several seconds to 5 minutes, preferably about 10seconds to about 1 minute, between applications of benzodiazepine drugto the same nostril. This allows time for the drug to cross the nasalmucosa and enter the blood stream. Multiple applications of meteredsprays to each nostril, optionally separated by a time interval, allowsadministration of a full therapeutic dose in increments small enough topermit full absorption of the benzodiazepine drug into the blood streamand avoid loss of drug down the back of the throat.

Mexazolam

The dosage of mexazolam varies by indication, however it is expectedthat a therapeutic dose will be in the range of about 0.1 to about 10,preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferablyfrom 2 to 8, and in some preferred embodiments about 4 to about 6 timesper day. Mexazolam may be manufactured using the process disclosed inU.S. Pat. No. 3,722,371, which is incorporated herein by reference inits entirety.

As a nasal formulation, mexazolam may be administered in 25 to 250 0_,metered sprays. In some preferred embodiments, mexazolam is administeredin 50 to 150 μL, especially about 100 μL, metered sprays. In someembodiments, a first metered spray is applied to a first nostril and ifnecessary a second metered spray is applied to a second nostril. In someoptional embodiments, a third metered spray is applied to the firstnostril. In some embodiments, a fourth metered spray is applied to thesecond nostril. In some embodiments, additional metered sprays areapplied to alternating nostrils until the full target therapeutic dosehas been administered to the patient. In some embodiments, there is atime increment of from several seconds to 5 minutes, preferably about 10seconds to about 1 minute, between applications of benzodiazepine drugto the same nostril. This allows time for the drug to cross the nasalmucosa and enter the blood stream. Multiple applications of meteredsprays to each nostril, optionally separated by a time interval, allowsadministration of a full therapeutic dose in increments small enough topermit full absorption of the benzodiazepine drug into the blood streamand avoid loss of drug down the back of the throat.

Midazolam

The dosage of midazolam varies by indication, however it is expectedthat a therapeutic dose will be in the range of about 0.1 to about 20,preferably about 0.2 to about 10 mg per dose, from 1 to 8, preferablyfrom 2 to 8, and in some preferred embodiments about 4 to about 6 timesper day. Midazolam may be manufactured using the process disclosed inone of U.S. Pat. No. 4,280,957 or 5,831,089, each of which isincorporated herein by reference in its entirety.

As a nasal formulation, midazolam may be administered in 25 to 250 μLmetered sprays. In some preferred embodiments, midazolam is administeredin 50 to 150 μL, especially about 100 μL, metered sprays. In someembodiments, a first metered spray is applied to a first nostril and ifnecessary a second metered spray is applied to a second nostril. In someoptional embodiments, a third metered spray is applied to the firstnostril. In some embodiments, a fourth metered spray is applied to thesecond nostril. In some embodiments, additional metered sprays areapplied to alternating nostrils until the full target therapeutic dosehas been administered to the patient. In some embodiments, there is atime increment of from several seconds to 5 minutes, preferably about 10seconds to about 1 minute, between applications of benzodiazepine drugto the same nostril. This allows time for the drug to cross the nasalmucosa and enter the blood stream. Multiple applications of meteredsprays to each nostril, optionally separated by a time interval, allowsadministration of a full therapeutic dose in increments small enough topermit full absorption of the benzodiazepine drug into the blood streamand avoid loss of drug down the back of the throat.

Temazepam

The dosage of temazepam varies by indication, however it is expectedthat a therapeutic dose will be in the range of about 1 to about 50,preferably about 5 to about 30 mg per dose, from 1 to 8, preferably from2 to 8, and in some preferred embodiments about 4 to about 6 times perday. Temazepam may be manufactured using the process disclosed in U.S.Pat. No. 3,340,253 or 3,374,225, each of which is incorporated herein byreference in its entirety.

As a nasal formulation, temazepam may be administered in 25 to 250 ut,metered sprays. In some preferred embodiments, temazepam is administeredin 50 to 150 μL, especially about 100 μL, metered sprays. In someembodiments, a first metered spray is applied to a first nostril and ifnecessary a second metered spray is applied to a second nostril. In someoptional embodiments, a third metered spray is applied to the firstnostril. In some embodiments, a fourth metered spray is applied to thesecond nostril. In some embodiments, additional metered sprays areapplied to alternating nostrils until the full target therapeutic dosehas been administered to the patient. In some embodiments, there is atime increment of from several seconds to 5 minutes, preferably about 10seconds to about 1 minute, between applications of benzodiazepine drugto the same nostril. This allows time for the drug to cross the nasalmucosa and enter the blood stream. Multiple applications of meteredsprays to each nostril, optionally separated by a time interval, allowsadministration of a full therapeutic dose in increments small enough topermit full absorption of the benzodiazepine drug into the blood streamand avoid loss of drug down the back of the throat.

Those skilled in the art will be aware that a systematic,therapeutically effective amount of benzodiazepine drugs for treatingthe aforementioned disorders will vary with age, size, weight, andgeneral physical condition of the patient as well as the severity of thedisease. Frequency of administration will likewise vary with theformulation of the composition and it can be adjusted so that anysuitable number of doses per day may be used.

EXAMPLES

The invention will now be illustrated with reference to the followingillustrative, non-limiting examples.

Example 1

A pharmaceutical composition comprising diazepam is prepared. It isformulated as a solution to be delivered via a nasal delivery device.The composition is used to treat or prevent seizures associated withepilepsy in adults. Treatment is administered either before or after aseizure has begun. If the patient is seizing, it is administered as 1puff from any nasal delivery device (1 puff at 5.0 mg/puff (5.0 mg/0.1mL and 0.1 mL/puff)) every 5 minutes until cessation of the seizure.However, it can be given as 1 puff per nostril in each nostril (2 puffsat 2.5 mg/puff (5.0 mg/0.1 mL and 0.05 mL/puff)) every 5 minutes untilcessation of the seizure. The composition according to this example isset forth in the following table.

TABLE 1-1 5.0 mg/0.1 mL Diazepam 70.0 mg α-tocopherol 0.1 mL ethanol (qsad to 0.1 mL)

Example 2

A pharmaceutical composition comprising diazepam is prepared. It isformulated as a solution to be delivered via a nasal delivery device.The composition is used to treat or prevent seizures associated withepilepsy in children. Treatment is administered either before or after aseizure has begun. If the patient is seizing, it is administered as 1puff from any nasal delivery device (1 puff at 2.0 mg/puff (2.0 mg/0.1mL and 0.1 mL/puff)). If the seizure fails to stop another dose may beadministered after 5 minutes. However, it can be given as 1 puff pernostril in each nostril (2 puffs at 1.0 mg/puff (2.0 mg/0.1 mL and 0.05mL/puff)). If the seizure fails to stop another dose may be administeredafter 5 minutes. The composition according to this example is set forthin the following table.

TABLE 2-1 2.0 mg/0.1 mL Diazepam 70.0 mg α-tocopherol 0.1 mL ethanol (qsad to 0.1 mL)

Example 3 Formulation of Diazepam Solutions

In general, benzodiazepine solutions may be formulated by combining oneor more natural or synthetic tocopherols or tocotrienols and one or morelower alcohols or glycols and mixing until a homogeneous mixture isformed, adding the benzodiazepine drug to the homogeneous mixture,heating and mixing the ingredients until the benzodiazepine is fullydissolved in the homogeneous mixture, cooling the mixture, and bringingthe mixture to its final mass or volume with lower alcohol or glycol.

Two different diazepam solutions were formulated by the foregoingprocess. Vitamin E USP and dehydrated ethanol USP were combined in theamounts set forth in the following table and mixed to form a homogeneousmixture. Diazepam in the amounts set forth in the following table wasthen added to the homogeneous mixture. The ingredients were heated to40-45° C. with mixing until the diazepam was fully dissolved, therebyforming a solution. The solution was cooled to 20-25° C., whereupon thesolution was brought to its final target weight with dehydrated ethanolUSP and the solution was mixed thoroughly to assure homogeneity. Thesolution was then sampled for in-process testing and packaged in 3 mLamber glass vials.

TABLE 3-1 Diazepam Solutions - 70 mg/mL Solution 00 Solution 02 (65%Vitamin E) (80% Vitamin E) Concentration Concentration Component (mg/mL)(mg/mL) Diazepam USP 70.0 70.0 Vitamin E USP 650.0 800.0 DehydratedEthanol USP q.s. to 1 mL q.s. to 1 mL

Additional solutions of diazepam at varying concentrations are made in asimilar manner, by varying the amount of diazepam and the relativeamounts of Vitamin E and ethanol. Other benzodiazepine solutions aremade by substituting one or more benzodiazepines for diazepam. Otheringredients, such as alkyl glycoside, can be added at a suitable step inthe process (e.g. before or concurrently with the addition ofbenzodiazepine).

Example 4 Formulation of Diazepam Suspensions

In general, benzodiazepine suspensions are formulated by micronizingbenzodiazepine and combining the benzodiazepine with a carrier. Thecarrier is prepared by combining one or more lower alcohols or glycolswith water, adding a natural or synthetic tocopherol or tocotrienol,heating the mixture until the tocopherol or tocotrienol is dissolved,adding one or more parabens and mixing until the parabens are dissolvedand cooling the carrier. Once the benzodiazepine is added to thecarrier, additional excipients, such as surfactants, can optionally beadded and dissolved in the carrier. The suspension is then brought up toits final mass or volume with water.

Two different diazepam suspensions were formulated by the foregoinggeneral process. Two different diazepam particle sizes were prepared—A:a small particle size by prepared by high pressure micronization, and B:a large particle size prepared by low pressure micronization. Thecarrier was prepared by combining propylene glycol USP and purifiedwater USP, then adding Vitamin E Polyethylene Glycols Succinate NF, thenmixing and heating the combined ingredients to about 45° C. Mixing wascontinued until the Vitamin E Polyethylene Glycol Succinate was fullydissolved. The carrier was then cooled to 20-25° C. The micronizeddiazepam (A and B) was then added to the carrier with vigorous mixinguntil the diazepam was fully dispersed in the carrier.Polyvinylpyrrolidone Povidone USP/NF was then added to the mixture andmixed until fully dissolved. The suspension was then brought up toweight with purified water USP. The suspension was then mixed untilhomogeneous, sampled for in-process testing, and packaged in 3 mL amberglass bottles.

TABLE 4-1 Diazepam Suspension Formulations Suspension 03 Suspension 01(200 mg/mL (100 mg/mL Diazepam) Diazepam) Concentration ConcentrationComponent (mg/mL) (mg/mL) Diazepam USP 200.00 100.00 Vitamin EPolyethylene 100.0 100.0 Glycol Succinate NF Methylparaben NF 2.0 2.0Propylparaben NF 0.5 0.5 Propylene Glycol USP 100.0 100.0 PovidoneUSP/NF 25.0 25.0 Purified Water USP/EP q.s. to 1 mL q.s. to 1 mL

Additional suspensions of diazepam at varying concentrations are made ina similar manner, by varying the amount of diazepam and optionally otherexcipients. Other benzodiazepine suspensions are made by substitutingone or more benzodiazepines for diazepam. Other ingredients, such asalkyl glycoside, can be added at a suitable step in the process. Forexample, an alkylglycoside may be added to the carrier duringcompounding of the carrier, or may be added to the suspension mixtureconcurrently with or after addition of the povidone.

Example 5 Stability of Diazepam Solutions and Suspensions

Solutions 00 and 02 (Example 3) and Suspensions 01 and 03 (Example 4)were set up on stability at 25° C./60% RH, 30° C./65% RH and 40° C./75%RH. One batch each of four different formulations, packaged in 3-mlvials with screw-top closures, along with corresponding actuators, wereset up at three storage conditions. They are listed in Table 1 withtheir corresponding Particle Sciences initial sample control numbers.

TABLE 5-1 Summary of PSI sample control numbers 25° C./60% 30° C./65%40° C./75% Formulation # RH RH RH Solution 00 - 70 mg/ml 083101.01083101.02 083101.02 solution, 65% Vitamin E Solution 02 - 70 mg/ml083102.01 083102.02 083102.03 solution, 80% vitamin E Suspension 01 -083103.01 083103.02 083103.03 100 mg/ mi suspension Suspension 03 -083104.01 083104.02 083104.03 200 mg/ml suspension

Samples were tested for spray content uniformity, spray volume, diazepamcontent, diazepam related substances, and methylparaben andpropylparaben assay (suspension samples only). Unit weights weredetermined as per USP <755>.

Summaries of the average assay values and all other results are given inTables 5-4, 5-5, 5-6 and 5-7. The results for the initial, 1-month and3-month time points are also shown for comparison. Individual spraycontent uniformity results are given in Tables 5-8, 5-9, 5-10, 5-11,5-12, 5-13, 5-14, and 5-15.

In general, all of the assays and the other results are similar to theinitial data, with the exceptions of diazepam related compounds A and B.

Related compound A did not meet the specification of not more than (NMT)0.01% for some samples (see Table 2). Related compound A has increasedwith time and temperature.

TABLE 5-2 Summary of related compound A T6M results 25° C./60% 30°C./65% 40° C./75% Solution/Suspension # RH RH RH Solution 00 Meets0.058% 0.051% specification Solution 02 Meets Meets Meets specificationspecification specification Suspension 01 0.038% 0.046% 0.157%Suspension 03 0.019% 0.029% 0.081%

Related compound B is also increasing with time and temperature, and nowfails specification of NMT 0.1% at 40° C. condition for both suspensionand one solution formulation. Only formulation 2602 meets all impurityspecifications.

TABLE 5-3 Summary of related compound B T6M results Solution/ Suspension# 25° C./60% RH 30° C./65% RH 40° C./75% RH Solution 00 Meets Meets0.398% specification specification Solution 02 Meets Meets Meetsspecification specification specification Suspension 01 Meets Meets0.289% specification specification Suspension 03 Meets Meets 0.123%specification specification

TABLE 5-4 Summary of Solution 00 results Solution 00, 1 1 1 3 3 3 6 6 670 mg/mI, month month month month month month month month month 65% 25°C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./Vitamin E Specifications Initial 60% RH 65% RH 75% RH 60% RH 65% RH 75%RH 60% RH 65% RH 75% RH Description Yellow to Amber Amber Amber AmberAmber Amber Amber Amber Amber Amber orange solution solution solutionsolution solution solution solution solution solution solution solutionIdentification- Conforms to pass N/A N/A N/A N/A N/A N/A N/A N/A N/A UVreference std. UV and RT Assay 90.0 to 100.1 100.3 93.9 98.8 96.3 96.9101.2 97.5 94.6 100.6 Diazepam 110.0% (%) Impurities (%)⁽¹⁾ NordazepamNMT 0.3% 0.005 0.01 0.014 0.019 0.013 0.013 0.013 0.013 0.013 0.013Related NMT 0.1% ND 0.002 0.007 0.03 0.008 0.016 0.089 0.024 0.098 0.398Compound B Related NMT 0.01% 0.002 0.002 0.004 0.011 0.002 0.002 0.010.005 0.058 0.051 Compound A Unknown NMT 0.1% 0.011 0.012 0.014 0.020.037 0.039 0.047 0.035 0.066 0.055 Total NMT 1.0% 0.0 0.0 0.0 0.1 0.10.1 0.2 0.1 0.2 0.5 Microbial Meets USP pass N/A N/A N/A N/A N/A N/Apass not not Limits {61} tested tested Fill weight report results 1.1081.105 1.111 1.112 1.109 1.109 1.113 1.103 1.111 1.109 (g) Fill volumereport results 1.192 1.189 1.195 1.196 1.193 1.193 1.198 1.187 1.1951.193 (ml) Spray report results 133.9 140.7 146.8 140.5 149.1 143.5139.6 131.4 not 136.4 delivered tested (μl) Average report results 95.0101.2 100.4 99.4 99.7 94.6 99.4 95.7 not 108.7 Spray tested Content (%)Viscosity report results 0.14 0.086 0.12 0.12 0.096 0.14 0.12 0.12 0.110.11 (Pa * s) ⁽¹⁾LOQ is approximately 0.006%, LOD is approximately0.002%. Results below LOQ are reported in this table for trendingpurposes.

TABLE 5-5 Summary of Solution 02 results 1 1 1 3 3 3 6 6 6 Solution 02,month month month month month month month month month 70 mg/mI, 25° C./30° C./ 40° C./ 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ 65% 60%65% 75% 60% 65% 75% 60% 65% 75% Vitamin E Specifications Initial RH RHRH RH RH RH RH RH RH Description Yellow Amber Amber Amber Amber AmberAmber Amber Amber Amber Amber to sol'n sol'n sol'n sol'n sol'n sol'nsol'n sol'n sol'n sol'n orange sol'n Identification- Conforms pass N/AN/A N/A N/A N/A N/A N/A N/A N/A UV to reference std. UV and RT Assay90.0 to 100.5 94.9 96.2 103.3 98.0 97.2 99.6 97.0 94.3 100.3 Diazepam110.0% (%) Impurities (%)⁽¹⁾ Nordazepam NMT 0.003 0.004 0.005 0.0060.005 0.005 0.006 0.005 0.004 0.005 0.3% Related NMT ND 0.002 0.0030.006 0.003 0.005 0.032 0.007 0.020 0.058 Compound B 0.1% Related NMT0.003 0.002 0.002 0.003 0.002 0.002 0.004 0.003 0.009 0.007 Compound A0.01% Unknown NMT 0.01 0.012 0.014 0.018 0.019 0.025 0.032 0.014 0.0200.018 0.1% Total NMT 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.1 0.1 1.0%Microbial Meets pass N/A N/A N/A N/A N/A N/A pass not not Limits USPtested tested {61} Fill weight report 1.135 1.117 1.128 1.123 1.1161.133 1.137 1.124 1.133 1.127 (g) results Fill volume report 1.184 1.1651.177 1.172 1.164 1.182 1.186 1.172 1.183 1.176 (ml) results Sprayreport 115.0 137.5 137.6 133.1 143.9 136.3 143.8 129.3 not 124.2delivered results tested (μl) Average report 98.6 97.6 97.7 100.7 98.794.7 100.5 95.8 not 97.1 Spray results tested Content (%) Viscosityreport 0.69 0.68 0.64 0.68 0.63 0.65 0.64 0.61 0.55 0.56 (Pa * s)results ⁽¹⁾LOQ is approximately 0.006%, LOD is approximately 0.002%.Results below LOQ are reported in this table for trending purposes.

TABLE 5-6 Summary of Suspension 01 results 1 1 1 3 3 3 6 6 6 month monthmonth month month month month month month Suspension 25° C./ 30° C./ 40°C./ 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ 01, Speci- 60% 65%75% 60% 65% 75% 60% 65% 75% 100 mg/mI fications Initial RH RH RH RH RHRH RH RH RH Description Cloudy to White White White White White WhiteWhite White pale yellow white dispersion dispersion dispersiondispersion dispersion dispersion dispersion dispersion yellow dispersionsolution dispersion Identification- Conforms Pass N/A N/A N/A N/A N/AN/A N/A N/A N/A UV to reference std. UV and RT Assay 90.0 to 102.8 102.6100.9 104.3 101.3 101.8 103.6 100.7 104.3 99.4 Diazepam 110.0% (%)Impurities (%)⁽¹⁾ Nordazepam NMT ND ND ND ND ND ND ND ND ND ND 0.3%Related NMT ND ND ND 0.004 ND 0.004 0.053 0.005 0.013 0.289 Compound B0.1% Related NMT ND 0.01 0.02 0.034 0.026 0.036 0.08 0.038 0.046 0.157Compound A 0.01% Unknown NMT 0.008 0.008 0.008 0.008 0.008 0.007 0.0070.008 0.007 0.018 0.1% Total NMT 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.1 0.51.0% Methylparaben 80.0%- 97.7 100.2 92.1 100.3 101.4 100.6 101.6 106.0103.2 103.2 (%) 115.% Propylparaben 80.0% 100.2 100.5 92.2 99.2 100.6 99100 98.5 97.6 96.7 (%) 115.0% Microbial Meets Pass N/A N/A N/A N/A N/AN/A pass not not Limits USP {61} tested tested Fill weight report 1.2541.252 1.252 1.244 1.246 1.248 1.247 1.245 1.242 1.235 (g) results Fillvolume report 1.198 1.196 1.196 1.188 1.191 1.193 1.191 1.190 1.1871.180 (ml) results Spray report 132.5 131.2 126 123.9 137.6 137.8 136.3140.0 not 137.6 delivered results tested (μl) Average report 92.2 94.291.1 89.9 101.5 100.4 95.3 101.8 not 95.94 Spray results tested Content(%) Viscosity report 0.0098 0.0098 0.0092 0.0090 0.0092 0.0093 0.00890.0082 0.0080 0.0092 (Pa * s) results ⁽¹⁾LOQ is approximately 0006%, LODis approximatelyo.002%. Results below LOQ are reported in this table fortrending purposes.

TABLE 5-7 Summary of Suspension 03 results 1 1 1 3 3 3 6 6 6 month monthmonth month month month month month month Suspension 25° C./ 30° C./ 40°C./ 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ 03, Speci- 60% 65%75% 60% 65% 75% 60% 65% 75% 200 mg/mL fications Initial RH RH RH RH RHRH RH RH RH Description Cloudy to White White White White White WhiteWhite White pale yellow white dispersion dispersion dispersiondispersion dispersion dispersion dispersion dispersion yellow dispersiondispersion dispersion Identification- Conforms to Pass N/A N/A N/A N/AN/A N/A N/A N/A N/A UV reference std. UV and RT Assay 90.0 to 100.7101.2 98.9 101.6 102.6 103.6 103.1 100.5 98.9 100.1 Diazepam 110.0% (%)Impurities (%)⁽¹⁾ Nordazepam NMT 0.3% ND ND ND ND ND ND ND ND ND NDRelated NMT 0.1% ND ND ND ND 0.002 ND 0.023 0.002 0.008 0.123 Compound BRelated NMT 0.01% ND 0.005 0.01 0.017 0.017 0.012 0.039 0.019 0.0290.081 Compound A Unknown NMT 0.1% 0.008 0.008 0.008 0.008 0.008 0.0080.008 0.008 0.007 0.008 Total NMT 1.0% 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.00.0 0.2 Methylparaben 80.0%- 93.4 101.1 93.8 99.7 101.5 101.6 101.2103.5 97.2 102.1 (%) 115.% Propylparaben 80.0% 95.6 100.2 94 98.4 100.1101.3 99.2 97.1 91.9 95.9 (%) 115.0% Microbial Meets USP Pass N/A N/AN/A N/A N/A N/A pass not not Limits {61} tested tested Fill weightreport 1.276 1.28 1.259 1.272 1.279 1.279 1.276 1.280 1.262 1.260 (g)results Fill volume report 1.186 1.19 1.171 1.183 1.19 1.19 1.187 1.1901.173 1.172 (ml) results Spray report 112.4 137.4 134.3 119.9 138.9139.3 134.3 149.4 not 138.0 delivered results tested (μl) Average report82.8 99.3 97.3 86.7 98.6 102.3 96.2 98.2 not 98.7 Spray results testedContent (%) Viscosity report 0.021 0.017 0.017 0.019 0.016 0.016 0.0180.014 0.013 0.015 (Pa * s) results ⁽¹⁾LOQ is approximately 0.006%, LODis approximately 0.002%. Results below LOQ are reported in this tablefor trending purposes.

TABLE 5-8 Solution 00 25° C./60% RH spray content uniformity resultsWeight Weight Diazepam % Diazepam Sample Collected, g Actuated, gRecovered, mg Recovered 1 0.13061 0.13259 9.59355 97.89 2 0.132170.13451 9.78206 99.82 3 0.12365 0.13332 8.85797 90.39 4 0.12761 0.130729.39720 95.89 5 0.14702 0.15216 8.91438 90.96 6 0.13414 0.13702 9.2244294.13 7 0.12959 0.13384 9.84590 100.47 8 0.12367 0.14603 8.88093 90.62 90.13367 0.13425 9.92610 101.29 Average 0.13135 0.13716 9.380 95.72 St.Dev. 0.0070 0.0071 0.4309 4.3970 % RSD 5.35 5.20 4.59 4.59

TABLE 5-9 Solution 00 40° C./75% RH spray content uniformity resultsWeight Weight Diazepam % Diazepam Sample Collected, g Actuated, gRecovered, mg Recovered 1 0.14139 0.15111 10.57237 107.88 2 0.147310.15146 11.62831 118.66 3 0.14489 0.14684 10.94206 111.65 4 0.142370.14873 11.94883 121.93 5 0.12188 0.13415 9.78103 99.81 6 0.127560.13047 9.78347 99.83 7 0.13549 0.13841 10.45221 106.66 8 0.123230.12543 9.41177 96.04 9 0.14299 0.14517 11.35701 115.89 Average 0.136350.14131 10.653 108.70 St. Dev. 0.0097 0.0095 0.8884 9.0649 % RSD 7.146.76 8.34 8.34

TABLE 5-10 Solution 02 25° C./60% RH spray content uniformity resultsWeight Weight Diazepam % Diazepam Sample Collected, g Actuated, gRecovered, mg Recovered 1 0.12280 0.12611 8.88043 90.62 2 0.133180.13549 9.55581 97.51 3 0.13260 0.13452 9.71837 99.17 4 0.12064 0.123059.48123 96.75 5 0.13215 0.13582 9.34463 95.35 6 0.13559 0.13790 9.4872296.81 7 0.13158 0.13371 9.43613 96.29 8 0.13357 0.13495 9.79164 99.91 90.12165 0.12443 8.84732 90.28 Average 0.12931 0.13178 9.394 95.85 St.Dev. 0.0058 0.0056 0.3303 3.3701 % RSD 4.52 4.25 3.52 3.52

TABLE 5-11 Solution 02 40° C./75% RH spray content uniformity resultsWeight Weight Diazepam % Diazepam Sample Collected, g Actuated, gRecovered, mg Recovered 1 0.12336 0.12563 9.02005 92.04 2 0.057230.05792 9.43076 96.23 3 0.13554 0.13908 9.93829 101.41 4 0.13619 0.136799.87755 100.79 5 0.13227 0.13414 9.64403 98.41 6 0.13331 0.13515 9.80808100.08 7 0.13455 0.13844 9.31952 95.10 8 0.13314 0.13736 9.28106 94.70 90.13249 0.13387 9.32935 95.20 Average 0.12423 0.12649 9.517 97.11 St.Dev. 0.0254 0.0260 0.3148 3.2119 % RSD 20.45 20.57 3.31 3.31

TABLE 5-12 Suspension 01 25° C./60% RH spray content uniformity resultsWeight Weight Diazepam % Diazepam Sample Collected, g Actuated, gRecovered, mg Recovered 1 0.12873 0.12999 12.85366 91.81 2 0.140110.14247 13.68122 97.72 3 0.14515 0.14757 14.09449 100.67 4 0.132050.13347 14.18775 101.34 5 0.14554 0.14743 14.48202 103.44 6 0.144730.14682 14.39897 102.85 7 0.13229 0.13411 14.87853 106.28 8 0.143570.14581 14.82712 105.91 9 0.14741 0.14940 14.86732 106.20 Average0.13995 0.14190 14.252 101.80 St. Dev. 0.0070 0.0074 0.6602 4.7154 % RSD5.03 5.18 4.63 4.63

TABLE 5-13 Suspension 01 40° C./75% RH spray content uniformity resultsWeight Weight Diazepam % Diazepam Sample Collected, g Actuated, gRecovered, mg Recovered 1 0.14411 0.14869 13.04770 93.20 2 0.140660.14151 13.23277 94.52 3 0.13012 0.13485 13.78126 98.44 4 0.146670.14879 13.36970 95.50 5 0.14294 0.14338 12.54309 89.59 6 0.137970.14253 13.25396 94.67 7 0.13374 0.13594 13.41984 95.86 8 0.123880.12559 14.34944 102.50 9 0.13790 0.14011 13.88564 99.18 Average 0.137550.14015 13.431 95.94 St. Dev. 0.0073 0.0073 0.5223 3.7310 % RSD 5.285.19 3.89 3.89

TABLE 5-14 Suspension 03 25° C./60% RH spray content uniformity resultsWeight Weight Diazepam % Disazepam Sample Collected, g Actuated, gRecovered, mg Recovered 1 0.13604 0.13897 25.93418 92.62 2 0.146080.14792 26.21721 93.63 3 0.15294 0.15425 30.05570 107.34 4 0.147280.14910 25.78804 92.10 5 0.15352 0.15493 26.60721 95.03 6 0.152420.15401 29.51030 105.39 7 0.15118 0.15254 28.43104 101.54 8 0.153220.15556 28.03664 100.13 9 0.15197 0.15393 26.82906 95.82 Average 0.149410.15125 27.490 98.18 St. Dev. 0.0057 0.0053 1.5812 5.6472 % RSD 3.793.50 5.75 5.75

TABLE 5-15 Suspension 03 40° C./75% RH spray content uniformity resultsWeight Weight Diazepam % Disazepam Sample Collected, g Actuated, gRecovered, mg Recovered 1 0.13574 0.13797 28.14588 100.52 2 0.136390.13803 27.04437 96.59 3 0.14082 0.14195 26.78985 95.68 4 0.129620.13249 29.07192 103.83 5 0.12518 0.12683 27.39785 97.85 6 0.144230.14541 28.50133 101.79 7 0.13922 0.14096 27.34617 97.66 8 0.141460.14313 27.17415 97.05 9 0.14902 0.15344 27.20939 97.18 Average 0.137960.14002 27.631 98.68 St. Dev. 0.0073 0.0076 0.7642 2.7294 % RSD 5.285.43 2.77 2.77

Example 6

All of the solutions and suspensions described in Examples 3 and 4 areformulated as described in Examples 3 and 4, with the addition of asuitable amount of an alkyl glycoside, as described herein, such asdodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrosemonostearate, sucrose distearate, and/or combinations of two or morethereof, or marketed as Intravail® by Aegis Therapeutics, San Diego,Calif. The solutions and suspensions with added alkyl glycoside may thenbe put up on stability as described in Example 5, mutatis mutandis.

Example 7

The solutions and suspensions of Examples 3, 4 and 6 are evaluated forpharmacokinetics in a suitable animal model, such as in mice, rats,rabbits or dogs. First each animal (e.g. rabbit) is administered anamount of a benzodiazepine drug intravenously. The amount ofintravenously dosed benzodiazepine drug is selected to be less, e.g.roughly half, of what is considered an effective dose administerednasally. For example, the intravenous dose of diazepam administered torabbits is about 0.05 to about 0.2 mg/kg, e.g. about 0.1 mg/kg. Blood iscollected immediately before administration and at specific time pointspost-administration. Plasma blood levels of the drug are assayed foreach of the blood samples. After at least a one day washout period, eachanimal is administered, intranasally, an amount of a solution orsuspension as described in Examples 3, 4 and 6. Blood is collectedimmediately before administration and at substantially the same specifictime points as the IV dose post-administration. Pharmacokinetic curves(blood plasma concentration of drug versus time) are constructed for theintravenous route of administration and for each of the solutions andsuspensions administered by the intranasal administration route.

Toxicity is assessed by known means. In particular, histological samplesare collected from the nasal mucosal tissues of the test animals. Othertoxological methods are optionally employed as well.

Example 8

The solutions and suspensions of Examples 3, 4 and 6 are evaluated fortheir ability to deliver drug across the blood brain barrier in asuitable animal model, such as in mice, rats, rabbits or dogs. Eachanimal is administered, intranasally, an amount of a solution orsuspension as described in Examples 3, 4 and 6, with the solution orsuspension optionally containing an imaging agent, such as a dye, thatmay be used as a proxy for determining the ability of the drug to crossthe blood brain barrier. The drug or imaging agent is detected atselected time points after administration of the suspension or solutionto determine how well the drug or imaging agent crosses the blood brainbarrier. These results may be compared with analogous result obtainedwith an intravenous solution containing the drug or imaging agent.

Example 9

The above-described solutions and/or suspensions can be evaluated forpharmacokinetics in humans. Normal, healthy human test subjects areadministered an amount of the drug intravenously. The amount chosen forintravenous administration may be any amount, but is conveniently a dosethat is considered effective in treating seizure in humans. For example,an IV dose of diazepam administered to humans may be in the range of 1to 15 mg, e.g. about 7.5 mg. Blood is collected immediately beforeadministration and at selected time points after administration. Plasmablood levels of the drug are assayed for each of the blood samples.After at least a one day washout period, each subject is administered,intranasally, an amount of a solution or suspension as described herein.Blood is collected immediately before administration and atsubstantially the same time points after administration as theintravenous time points. Pharmacokinetic curves (blood plasmaconcentration of drug versus time) are constructed for the intravenousand intranasal administration routes.

Example 10

The above-described solutions and/or suspensions can be evaluated forefficacy in a suitable animal model. Briefly, for each dose ofsuspension or solution to be tested, a test animal is stimulated with aseizure inducing stimulus. The stimulus may be light, sound, chemical orother stimulus effective to induce seizure in the model animal. Once theanimal has begun to seize, a solution or suspension as described hereinis administered intranasally to the animal. The efficacy of the dose ofthe solution and/or suspension is evaluated based upon the animal'sresponse to the test dose. This procedure is repeated through sufficientiterations, and at sufficient numbers of doses, to identify a dose thatis considered effective to treat seizure by intranasal administration ofthe drug.

Example 11

A pharmaceutical composition comprising diazepam was prepared as acomposition formulated as a solution to be delivered via a nasaldelivery device. The solution was prepared according to the procedureoutlined in the flow diagram of FIG. 4. The ingredients used in the 100mg/mL diazepam solution are set forth in Table 11-1, below:

TABLE 11-1 Concentration Ingredient (% (w/v)) Diazepam 10.00% (w/v)α-tocopherol* 56.47% (w/v) Ethanol (dehydrated) q.s. ((~18.07) % (w/v))Intravail A3** 0.25% (w/v) Benzyl alcohol 10.50% (w/v) *Vitamin E,**Dodecyl maltoside

A batch of solution of Table 11-1 was prepared and subjected tostability testing at 25° C./60% R.H. for 12 months. The following tableprovides stability determinations for this batch at initial, 3 month, 6month and 12 month time points.

Initial % Label Test Parameter Claim (100 mg/mL) 1 Month 3 Month 6 MonthAppearance Pale amber to Amber Amber Amber amber solution solutionsolution solution Diazepam % 103.3 99.5 99.2 99.1 Label Claim

A batch of solution of Table 11-1 was prepared and subjected tostability testing at 30° C./65% R.H. (accelerated conditions) for 12months. The following table provides stability determinations for thisbatch at initial, 1 month and 12 month time points.

Initial % Label Test Parameter Claim (100 mg/mL) 1 Month 6 MonthAppearance Pale amber to Amber solution Amber solution amber solutionDiazepam % 103.3 97.8 99.7 Label Claim

A batch of solution of Table 11-1 was prepared and subjected tostability testing at 40° C./75% R.H. (accelerated conditions) for 12months. The following table provides stability determinations for thisbatch at initial, 3 month, 6 month and 12 month time points.

Initial % Label Test Parameter Claim (100 mg/mL) 1 Month 3 Month 6 MonthAppearance Pale amber to Amber Amber Amber amber solution solutionsolution solution Diazepam % 103.3 97.9 100.0 99.4 Label Claim

The suspension formulation is set forth in Table 11-2, below

Component Function Concentration (mg/mL) Diazepam Active 100.0 MethylParaben Preservative 2.0 Propyl Paraben Preservative 0.5 Intravail A3Absorption aid 2.5 Vitamin E TPGS Dispersant 10.0 Propylene GlycolDispersant 100.0 Povidone Suspending agent 5.0 Water Carrier q.s. to 1.0mL

A batch of suspension of Table 11-2 was prepared and subjected tostability testing at 25° C./60% R.H. for 3 months. The following tableprovides stability determinations for this batch at initial and 3 monthtime points.

Test Initial % Label Parameter Claim (100 mg/mL) 3 Month AppearanceOpaque white liquid Opaque white liquid Diazepam % Label Claim 104.4102.1

A batch of suspension of Table 11-2 was prepared and subjected tostability testing at 30° C./65% R.H. (accelerated conditions) for 1month. The following table provides stability determinations for thisbatch at initial and 1 month time points.

Initial % Label Claim Test Parameter (100 mg/mL) 1 Month AppearanceOpaque white liquid Opaque white liquid Diazepam % Label Claim 104.4102.9

A batch of suspension of Table 11-2 was prepared and subjected tostability testing at 40° C./75% R.H. (accelerated conditions) for 3months. The following table provides stability determinations for thisbatch at initial, 1 month and 3 month time points.

Test Initial % Label Parameter Claim (100 mg/mL) 1 Month 3 MonthAppearance Opaque white liquid Opaque white liquid White liquid Diazepam% 104.4 102.7 108.7 Label Claim

A three-period, three-treatment, six-sequence, randomized cross-overstudy was conducted in healthy volunteers. For each dose, each volunteerwas domiciled for at least 12 hours prior to each dose and until after a24 hour pharmacokinetic sample was collected. Single doses of 100 μL ofthe pharmaceutical compositions described in Tables 11-1 and 11-2 wereadministered to each volunteer as one spray to the left nostril of 100μL per spray. Pharmacokinetic samples were collected at 22 time pointsover 10 days. (PK time points: 2.5, 5, 10, 15, 20, 30 and 45 minutes, 1,1.5, 2, 4, 12, 24, 36, 48, 72, 96, 144, 192 and 240 hours after eachdose.) No serious adverse events were noted. PK data were compared withthose obtained with 5 mg of diazepam administered intravenously. The PKdata are summarized in Table 11-3 and FIGS. 1-3.

The solution of Table 11-1 and the suspension of Table 11-2 were foundto be well-tolerated with only mild adverse events reported. Thesolution of Table 11-1 was further found to have similar bioavailabilityto intravenous administration of diazepam (96% of i.v.) The intranasalformulation of Table 11-1 exhibited a Tmax of 1.5 hours, a Cmax ofapproximately 272 ng/mL. These results are comparable to those reportedin the literature for commercially available diazepam gel (Diastat®).

Solutions similar to those set forth in Table 11-1 can be preparedconsisting of: diazepam (5-15% (w/v)), dodecyl maltoside (0.01-1%(w/v)), vitamin E (45-65% (w/v)), ethanol (10-25% (w/v)) and benzylalcohol (5-15% (w/v)); diazepam (9-11% (w/v)), dodecyl maltoside(0.1-0.5% (w/v)), vitamin E (50-60% (w/v)), ethanol (15-22.5% (w/v)) andbenzyl alcohol (7.5-12.5% (w/v)); or diazepam (10% (w/v)), dodecylmaltoside (0.15-0.3% (w/v)), vitamin E (50-60% (w/v)), ethanol (17-20%(w/v)) and benzyl alcohol (10-12% (w/v)).

Solutions similar to those set forth in Table 11-1 achievebioavailability that is from about 80-125% of that achieved with thesame benzodiazepine administered intravenously, e.g. bioavailabilitythat is from about 90-110% of that achieved with the same benzodiazepineadministered intravenously or about 92.5 to 107.5% that obtained withthe same benzodiazepine administered intravenously. Such solutions maybe used in methods of treating a patient with a disorder which may betreatable with a benzodiazepine drug, such as seizure, epileptic seizureand/or breakthrough seizure. In some embodiments, solutions describedherein may be used to treat a disorder such as is treated with Diastat®diazepam gel.

A summary of pharmacokinetic data obtained for the solution and asuspension form of diazepam is shown below in Table 11-3:

TABLE 11-3 Summary of Pharmacokinetic Parameters for Intranasal (10 mg)and IV (5 mg) Diazepam Diazepam Nasal Spray (10 mg/100 μL) DiazepamInjection NRL-1.A Suspension NRL-1.B Solution 5 mg/mL IV Parameter^(a) nMean (SD)^(a) n Mean (SD)^(a) n Mean (SD)^(a) C_(max) (ng/mL) 24 221(78.6) 24 272 (100) 24 555 (316) T_(max) (h)^(b) 24 1.00 (0.6, 2.0) 241.50 (0.8, 4.0) 24 0.03 (0.03, 0.50) AUC_(0-t) (h × ng/mL) 24 5229(1463) 24 7340 (1882) 24 3832 (1150) AUC_(0-∞) (h × ng/mL) 20 5381(1409) 20 7338 (2072) 24 4104 (1318) λz (h⁻¹) 20 0.0142 (0.0053) 200.0155 (0.0046) 24 0.0142 (0.0055) t 1/2 (h) 20 56.2 (23.0) 20 49.2(16.9) 24 56.2 (21.0) ^(a)Mean values are presented as arithmetic means.^(b)Median (min, max) reported for T_(max)

The data collected in the study are further illustrated in FIGS. 1-3.FIG. 1 is a linear scale plot of the arithmetic mean of the plasmaconcentration of diazepam after intranasal (IN) administration of 10 mgof diazepam as the suspension of Table 11-2 and after IN administrationof 10 mg of diazepam as a solution of Table 11-1 compared to intravenous(IV) administration of 5 mg of diazepam. FIG. 2 is a semi-logarithmicscale plot of the same data shown in FIG. 1. FIG. 3 shows the first 24hours of data from FIG. 1 on a linear scale.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A pharmaceutical solution for nasaladministration consisting of: (a) a benzodiazepine drug; (b) one or morenatural or synthetic tocopherols or tocotrienols, or any combinationsthereof, in an amount from about 30% to about 95% (w/w); (c) one or morealcohols or glycols, or any combinations thereof, in an amount fromabout 10% to about 70% (w/w); and (d) an alkyl glycoside, in apharmaceutically-acceptable formulation for administration to one ormore nasal mucosal membranes of a patient.
 2. The pharmaceuticalsolution of claim 1, wherein the benzodiazepine drug is dissolved in theone or more natural or synthetic tocopherols or tocotrienols, or anycombinations thereof, in an amount from about 30% to about 95% (w/w);and the one or more alcohols or glycols, or any combinations thereof, inan amount from about 10% to about 70% (w/w).
 3. The pharmaceuticalsolution of claim 2, wherein the benzodiazepine drug is selected fromthe group consisting of: alprazolam, brotizolam, chlordiazepoxide,clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil,flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam,oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam,loprazolam, any pharmaceutically-acceptable salts thereof, and anycombinations thereof.
 4. The pharmaceutical solution of claim 3, whereinthe benzodiazepine drug is diazepam, or a pharmaceutically-acceptablesalt thereof.
 5. The pharmaceutical solution of claim 1, containingabout 1 to about 20% (w/v) of benzodiazepine.
 6. The pharmaceuticalsolution of claim 5, containing about 1 to about 20% (w/v) of diazepam.7. The pharmaceutical solution of claim 1, wherein the one or morenatural or synthetic tocopherols or tocotrienols are selected from thegroup consisting of: α-tocopherol, β-tocopherol, γ-tocopherol,δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol,δ-tocotrienol, tocophersolan, any isomers thereof, any esters thereof,any analogs or derivatives thereof, and any combinations thereof.
 8. Thepharmaceutical solution of claim 1, wherein the one or more alcohols areselected from the group consisting of: ethanol, propyl alcohol, butylalcohol, pentanol, benzyl alcohol, any isomers thereof, or anycombinations thereof.
 9. The pharmaceutical solution of claim 1,containing two or more alcohols.
 10. The pharmaceutical solution ofclaim 1, containing ethanol (1-25% (w/v)) and benzyl alcohol (1-25%(w/v)).
 11. The pharmaceutical solution of claim 1, containing ethanol(10-22.5% (w/v)) and benzyl alcohol (7.5-12.5% (w/v)).
 12. Thepharmaceutical solution of claim 11, wherein the benzodiazepine ispresent in the pharmaceutical solution in a concentration from about 20mg/mL to about 200 mg/mL.
 13. The pharmaceutical solution of claim 1,wherein the one or more natural or synthetic tocopherols ortocotrienols, or any combinations thereof, is in an amount from about45% to about 85% (w/w).
 14. The pharmaceutical solution of claim 13,wherein the one or more natural or synthetic tocopherols ortocotrienols, or any combinations thereof, is in an amount from about50% to about 75% (w/w).
 15. The pharmaceutical solution of claim 1,wherein the one or more alcohols or glycols, or any combinationsthereof, is in an amount from about 15% to about 55% (w/w).
 16. Thepharmaceutical solution of claim 15, wherein the one or more alcohols orglycols, or any combinations thereof, is in an amount from about 25% toabout 40% (w/w).
 17. The solution of claim 1, consisting of diazepam(5-15% (w/v)), alkyl glycoside (0.01-1% (w/v)), vitamin E (45-65%(w/v)), ethanol (10-25% (w/v)) and benzyl alcohol (5-15% (w/v)).
 18. Thesolution of claim 1, wherein the pharmaceutically-acceptable formulationcomprises at least about 0.01% (w/w) of an alkyl glycoside.
 19. Thesolution of claim 18, wherein the pharmaceutically-acceptableformulation about 0.01% to 1% (w/w) of an alkyl glycoside, such asdodecyl maltoside.
 20. The solution of claim 1, consisting essentiallyof diazepam, vitamin E, ethanol, benzyl alcohol and dodecyl maltoside.21. The solution of claim 20, consisting of diazepam, vitamin E,ethanol, benzyl alcohol and dodecyl maltoside.
 22. The solution of claim21, consisting of about 56.47% (w/v) vitamin E, about 10.5% (w/v) benzylalcohol, about 10% (w/v) diazepam, about 0.25% (w/v) dodecyl maltoside,q.s. dehydrated ethanol.
 23. A method of treating a patient with adisorder which may be treatable with a benzodiazepine drug, comprising:administering to one or more nasal mucosal membranes of a patient apharmaceutical solution for nasal administration consisting of abenzodiazepine drug, one or more natural or synthetic tocopherols ortocotrienols, or any combinations thereof, in an amount from about 30%to about 95% (w/w); one or more alcohols or glycols, or any combinationsthereof, in an amount from about 10% to about 70% (w/w); and an alkylglycoside.
 24. The method of claim 23, wherein the benzodiazepine drugis dissolved in the one or more natural or synthetic tocopherols ortocotrienols, or any combinations thereof, in an amount from about 30%to about 95% (w/w); and the one or more alcohols or glycols, or anycombinations thereof, in an amount from about 10% to about 70% (w/w).25. The method of claim 24, wherein the natural or synthetic tocopherolsor tocotrienols is Vitamin E.
 26. The method of claim 23, wherein thebenzodiazepine drug is selected from the group consisting of:alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam,clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam,midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam,prazepam, quazepam, triazolam, temazepam, loprazolam, or anypharmaceutically-acceptable salts thereof, and any combinations thereof.27. The method of claim 26, wherein the benzodiazepine drug is diazepam,or a pharmaceutically-acceptable salt thereof.
 28. The method of claim23, wherein the solution contains about 1 to about 20% (w/v) ofbenzodiazepine.
 29. The method of claim 28, wherein the solutioncontains about 1 to about 20% (w/v) of diazepam.
 30. The method of claim23, wherein the one or more natural or synthetic tocopherols ortocotrienols are selected from the group consisting of: α-tocopherol,β-tocopherol, γ-tocopherol, 8-tocopherol, α-tocotrienol, β-tocotrienol,γ-tocotrienol, δ-tocotrienol, tocophersolan, any isomers thereof, anyesters thereof, any analogs or derivatives thereof, and any combinationsthereof.
 31. The method of claim 23, wherein the one or more alcoholsare selected from the group consisting of: ethanol, propyl alcohol,butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, and anycombinations thereof.
 32. The method of claim 23, wherein the solutioncontains two or more alcohols.
 33. The method of claim 23, wherein thesolution contains ethanol (1-25% (w/v)) and benzyl alcohol (1-25%(w/v)).
 34. The method of claim 33, wherein the benzodiazepine drug ispresent in the pharmaceutical solution in a concentration of from about10 mg/mL to about 250 mg/mL.
 35. The method of claim 34, wherein thebenzodiazepine drug is present in the pharmaceutical solution in aconcentration of from about 20 mg/mL to about 50 mg/mL.
 36. The methodof claim 23, wherein the pharmaceutical solution comprises one or morenatural or synthetic tocopherols or tocotrienols, or any combinationsthereof, in an amount from about 45% to about 85% (w/w).
 37. The methodclaim 36, wherein the pharmaceutical solution comprises one or morenatural or synthetic tocopherols or tocotrienols, or any combinationsthereof, in an amount from about 60% to about 75% (w/w).
 38. The methodof claim 23, wherein the pharmaceutical solution comprises one or morealcohols or glycols, or any combinations thereof, in an amount fromabout 15% to about 55% (w/w).
 39. The method of claim 38, wherein thepharmaceutical solution comprises one or more alcohols or glycols, orany combinations thereof, in an amount from about 25% to about 40%(w/w).
 40. The method of claim 23, wherein the solution contains ethanol(10-22.5% (w/v)) and benzyl alcohol (7.5-12.5% (w/v)).
 41. The method ofclaim 23, wherein the solution is in a pharmaceutically-acceptable sprayformulation.
 42. The method of claim 41, wherein the benzodiazepine isadministered in a therapeutically effective amount from about 1 mg toabout 20 mg.
 43. The method of claim 42, wherein said pharmaceuticalsolution is in a pharmaceutically-acceptable spray formulation havingvolume from about 10 μL to about 200 μL.
 44. The method of claim 43,wherein the administration of the pharmaceutical solution comprisesspraying at least a portion of the therapeutically effective amount ofthe benzodiazepine into at least one nostril.
 45. The method of claim43, wherein the administration of the pharmaceutical solution comprisesspraying at least a portion of the therapeutically effective amount ofthe benzodiazepine into each nostril.
 46. The method of claim 45,wherein the administration of the pharmaceutical solution comprisesspraying a first quantity of the pharmaceutical solution into the firstnostril, spraying a second quantity of the pharmaceutical solution intoa second nostril, and optionally after a pre-selected time delay,spraying a third quantity of the pharmaceutical solution into the firstnostril.
 47. The method of claim 46, further comprising, optionallyafter a pre-selected time delay, administering at least a fourthquantity of the pharmaceutical solution to the second nostril.
 48. Themethod of claim 46, wherein nasal administration of the pharmaceuticalsolution begins at any time before or after onset of symptoms of adisorder which may be treatable with the pharmaceutical solution. 49.The method of claim 23, wherein the solution contains at least about0.01% (w/w) of an alkyl glycoside.
 50. The method of claim 24, whereinthe solution contains about 0.01% to 1% (w/w) of an alkyl glycoside. 51.The method of claim 50, wherein the solution contains about 0.01% to 1%(w/w) of dodecyl maltoside.
 52. The method of claim 23, wherein thesolution consists essentially of diazepam, vitamin E, ethanol, benzylalcohol and dodecyl maltoside.
 53. The method of claim 23, wherein thesolution consists of diazepam, vitamin E, ethanol, benzyl alcohol anddodecyl maltoside.
 54. The method of claim 23, wherein the solutionconsists of about 56.47% (w/v) vitamin E, about 10.5% (w/v) benzylalcohol, about 10% (w/v) diazepam, about 0.25% (w/v) dodecyl maltoside,q.s. dehydrated ethanol.
 55. The method of one of claims 23-54, whereinthe solution consists of diazepam, alkyl glycoside, vitamin E, ethanol,and benzyl alcohol.
 56. The method of one of claims 23-54, wherein thesolution consists of diazepam (5-15% (w/v)), dodecyl maltoside (0.01-1%(w/v)), vitamin E (45-65% (w/v)), ethanol (10-25% (w/v)) and benzylalcohol (5-15% (w/v)).
 57. The solution of claim 17, consisting ofdiazepam (5-15% (w/v)), dodecyl maltoside (0.01-1% (w/v)), vitamin E(45-65% (w/v)), ethanol (10-25% (w/v)) and benzyl alcohol (5-15% (w/v)).58. The solution of claim 17, consisting of diazepam (9-11% (w/v)),dodecyl maltoside (0.1-0.5% (w/v)), vitamin E (50-60% (w/v)), ethanol(15-22.5% (w/v)) and benzyl alcohol (7.5-12.5% (w/v)).
 59. The solutionof claim 17, consisting of diazepam (10% (w/v)), dodecyl maltoside(0.15-0.3% (w/v)), vitamin E (50-60% (w/v)), ethanol (17-20% (w/v)) andbenzyl alcohol (10-12% (w/v)).
 60. The method of claim 23, wherein thesolution consists of diazepam (5-15% (w/v)), dodecyl maltoside (0.01-1%(w/v)), vitamin E (45-65% (w/v)), ethanol (10-25% (w/v)) and benzylalcohol (5-15% (w/v)).
 61. The method of claim 23, wherein the solutionconsists of diazepam (9-11% (w/v)), dodecyl maltoside (0.1-0.5% (w/v)),vitamin E (50-60% (w/v)), ethanol (15-22.5% (w/v)) and benzyl alcohol(7.5-12.5% (w/v)).
 62. The method of claim 23, wherein the solutionconsists of diazepam (10% (w/v)), dodecyl maltoside (0.15-0.3% (w/v)),vitamin E (50-60% (w/v)), ethanol (17-20% (w/v)) and benzyl alcohol(10-12% (w/v)).
 63. The method of one of claim 23-56 or 60-62, whereinsaid treatment achieves bioavailability that is from about 80-125% ofthat achieved with the same benzodiazepine administered intravenously.64. The method of claim 63, wherein said treatment achievesbioavailability that is from about 90-110% of that achieved with thesame benzodiazepine administered intravenously.
 65. The method of claim64, wherein said treatment achieves bioavailability that is from about92.5 to 107.5% that obtained with the same benzodiazepine administeredintravenously.